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Questions and Answers
What is the most widely used specific stain for amyloid?
What is the most widely used specific stain for amyloid?
What appearance does amyloid show under polarized light when stained with Congo red?
What appearance does amyloid show under polarized light when stained with Congo red?
Which organ is primarily affected in primary amyloidosis?
Which organ is primarily affected in primary amyloidosis?
What is the primary component of amyloid material?
What is the primary component of amyloid material?
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Which amyloid protein is associated with plasma cell tumors?
Which amyloid protein is associated with plasma cell tumors?
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What is the characteristic microscopic appearance of amyloid deposits?
What is the characteristic microscopic appearance of amyloid deposits?
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What is the role of Thioflavin T in the context of amyloidosis?
What is the role of Thioflavin T in the context of amyloidosis?
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What condition leads to increased synthesis of serum amyloid-associated (SAA) protein?
What condition leads to increased synthesis of serum amyloid-associated (SAA) protein?
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Which staining method gives a rose pink appearance for amyloid?
Which staining method gives a rose pink appearance for amyloid?
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Which protein is derived from the amyloid beta precursor protein (AbPP)?
Which protein is derived from the amyloid beta precursor protein (AbPP)?
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Familial amyloid polyneuropathies are associated with which amyloid protein?
Familial amyloid polyneuropathies are associated with which amyloid protein?
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Which of these tissues does amyloid predominantly deposit in the kidneys?
Which of these tissues does amyloid predominantly deposit in the kidneys?
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What is a characteristic feature of amyloid fibrils?
What is a characteristic feature of amyloid fibrils?
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What happens to the appearance of an affected organ with a large accumulation of amyloid?
What happens to the appearance of an affected organ with a large accumulation of amyloid?
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In which situation is B2-microglobulin amyloidosis most commonly found?
In which situation is B2-microglobulin amyloidosis most commonly found?
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What defines primary systemic amyloidosis?
What defines primary systemic amyloidosis?
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What type of amyloid is primarily associated with blood dyscrasia, such as multiple myeloma?
What type of amyloid is primarily associated with blood dyscrasia, such as multiple myeloma?
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Which of the following components makes up about 5% of the amyloid material?
Which of the following components makes up about 5% of the amyloid material?
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According to the classification of amyloidosis based on etiology, which type is considered inherited?
According to the classification of amyloidosis based on etiology, which type is considered inherited?
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What is the main role of Apolipoprotein-E (apoE) in relation to amyloid?
What is the main role of Apolipoprotein-E (apoE) in relation to amyloid?
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Which of the following conditions is NOT typically associated with secondary amyloidosis?
Which of the following conditions is NOT typically associated with secondary amyloidosis?
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Which type of amyloid deposition is characterized by proximity to the cells producing the abnormal protein?
Which type of amyloid deposition is characterized by proximity to the cells producing the abnormal protein?
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What type of amyloid protein is typically found in senile systemic amyloidosis?
What type of amyloid protein is typically found in senile systemic amyloidosis?
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What triggers the liver cells to form serum amyloid associated protein in cases of secondary amyloidosis?
What triggers the liver cells to form serum amyloid associated protein in cases of secondary amyloidosis?
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What is the primary cause of hemodialysis-associated amyloidosis in patients with chronic renal failure?
What is the primary cause of hemodialysis-associated amyloidosis in patients with chronic renal failure?
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Which type of amyloidosis is characterized by recurrent attacks of fever and inflammation of serosal surfaces?
Which type of amyloidosis is characterized by recurrent attacks of fever and inflammation of serosal surfaces?
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What type of protein is primarily involved in familial amyloidotic neuropathies?
What type of protein is primarily involved in familial amyloidotic neuropathies?
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Which amyloid type is associated with localized amyloidosis due to endocrine tumors?
Which amyloid type is associated with localized amyloidosis due to endocrine tumors?
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Which clinical manifestation is commonly associated with renal involvement in systemic amyloidosis?
Which clinical manifestation is commonly associated with renal involvement in systemic amyloidosis?
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What diagnostic method is considered definitive for identifying amyloid deposits in tissues?
What diagnostic method is considered definitive for identifying amyloid deposits in tissues?
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What is a common initial symptom of systemic amyloidosis?
What is a common initial symptom of systemic amyloidosis?
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In which organ is biopsy most commonly performed to detect systemic amyloidosis?
In which organ is biopsy most commonly performed to detect systemic amyloidosis?
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Study Notes
Amyloidosis
- A group of diseases with common deposition of amyloid protein in the extracellular space of various tissues and organs.
- Amyloid is a pathological protein with an insoluble, linear, rigid, and non-branching fibril structure.
- Fibril proteins account for about 95% of amyloid.
- Non-fibrillar components account for about 5% and consist of proteoglycans, glycosaminoglycans, serum P components, and others.
Fibril proteins
- Two major types: AL and AA.
- Over 20 minor forms.
Major forms
-
AL (amyloid light chain):
- Composed of immunoglobulin (Ig) light chains or fragments of light chains.
- Produced by plasma cells.
- Associated with monoclonal B cell proliferation (e.g., plasma cell tumors).
- Seen in primary systemic amyloidosis.
-
AA (amyloid-associated):
- Non-immunoglobulin protein.
- Derived from a larger precursor in the serum: SAA (serum amyloid-associated) protein, synthesized by the liver.
- Increased SAA protein production is triggered by cytokines (e.g., IL-6, IL-1) during inflammation.
- Associated with chronic inflammation (secondary amyloidosis).
Minor forms
-
Transthyretin (TTR):
- Normal serum protein that transports thyroxine and retinol.
- Mutations in the TTR gene lead to structural alterations and misfolding.
- Found in familial amyloid polyneuropathies.
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Amyloid B 2-microglobulin (AB2M):
- A normal serum protein.
- Deposited in amyloidosis of patients on long-term hemodialysis.
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Amyloid B-peptide (AB):
- Distinct from AB2M.
- Deposited in cerebral amyloid angiopathy and neurofibrillary tangles in Alzheimer's disease.
- Derived from amyloid beta precursor protein (AbPP).
-
Endocrine amyloid:
- Derived from hormone precursor proteins, for example, amyloid from pro-calcitonin (ACal), islet amyloid polypeptide (AIAPP, amylin), pro-insulin (AIns), prolactin (APro), etc.
-
Amyloid of prion protein (APrP):
- Derived from the precursor prion protein, a plasma membrane glycoprotein.
- Prion proteins are infectious particles without RNA or DNA.
Non-fibrillar components
- About 5% of amyloid material.
- Include:
-
Amyloid P (AP) component:
- Synthesised in the liver.
- Found in all types of amyloid.
- Derived from circulating serum amyloid P-component, a glycoprotein similar to normal serum α1-glycoprotein.
-
Apolipoprotein-E (apoE):
- A regulator of lipoprotein metabolism.
- Found in all types of amyloid.
-
Sulfated glycosaminoglycans (GAGs):
- Constituents of matrix proteins.
-
Amyloid P (AP) component:
Classification
-
Distribution of amyloid deposition:
- Generalized (Systemic): Amyloid deposition occurs in distant sites from the cells producing the abnormal proteins.
- Localized: Amyloid deposition occurs near the cells producing it.
-
Etiology:
- Inherited (primary): Amyloid deposition is due to genetic factors.
- Acquired (secondary): Amyloid deposition is caused by acquired factors.
-
Type of amyloid fibril protein:
- Each type is named based on its specific protein component (e.g., AL, AA, TTR, AB2M).
Systemic Amyloidosis
- Subclassified into:
Primary Amyloidosis
- Due to blood dyscrasia, for example, multiple myeloma (a malignant tumor of plasma cells).
- Systemic amyloid deposition of AL type.
- Malignant plasma cells secrete excessive immunoglobulin light chains called Bence Jones protein, which is also found in serum and urine.
Secondary Amyloidosis
- Systemic amyloid deposition of AA type.
- Causes include:
- Infections, e.g., Tuberculosis.
- Non-infectious chronic inflammatory processes, for example:
- Bronchiectasis
- Chronic osteomyelitis
- Rheumatoid arthritis
- Inflammatory bowel diseases.
- Chronic inflammation activates macrophages, resulting in secretion of IL-1 and IL-6, which stimulate liver cells to produce SAA protein. SAA protein forms AA amyloid.
Senile Systemic Amyloidosis
- Systemic amyloid deposition in elderly individuals, usually between 70 and 80 years old.
- The amyloid is composed of the normal TTR molecule.
Hemodialysis-associated Amyloidosis
- Occurs in patients with chronic renal failure undergoing long-term hemodialysis.
- High serum levels of B2-microglobulin, which cannot be filtered through dialysis membranes, are deposited as amyloid.
Hereditary or Familial Amyloidosis
- A heterogeneous group of rare genetic disorders occurring in specific geographic regions.
Familial Mediterranean Fever
- Autosomal recessive disorder.
- Characterized by recurrent bouts of fever accompanied by inflammation of serosal surfaces (peritoneum, pleura, and synovial membrane).
- The gene encodes a protein called pyrin, which regulates inflammatory reactions.
- High levels of pro-inflammatory cytokines (IL-1) are produced.
- The amyloid fibril proteins are of AA type, likely due to recurrent episodes of inflammation.
Familial Amyloidotic Neuropathies
- Characterized by amyloid deposition in peripheral and autonomic nerves.
- Fibrils are composed of mutant TTRs.
Localized Amyloidosis
- Amyloid deposits are restricted to a single organ or tissue without involvement of other sites.
- It forms localized nodular masses, for example, in the lung, larynx, skin, and tongue.
- The amyloid deposit is usually AL type.
- Some localized lesions are associated with endocrine tumors (endocrine amyloid) like medullary carcinoma of the thyroid and carcinoma of the stomach.
Clinical Features
- Initial manifestations may be nonspecific (e.g., weakness, weight loss).
- Later, specific symptoms develop, related to renal, cardiac, and gastrointestinal involvement.
Renal Involvement
- Proteinuria, sometimes leading to nephrotic syndrome.
- In advanced stages, glomerular obliteration causes renal failure and uremia.
Cardiac Amyloidosis
- May lead to congestive heart failure, conduction disturbances, and arrhythmias.
Gastrointestinal Amyloidosis
- Can be asymptomatic or manifest as malabsorption, diarrhea, and digestive disturbances.
Diagnosis
-
Biopsy: Histologic demonstration of amyloid deposits in tissues.
- Common sites for biopsy in systemic amyloidosis are the kidney, rectum, or gingival tissues.
- The rectum is the preferred site for biopsy.
- Examination of abdominal fat aspirates stained with Congo red is specific but less sensitive.
- Bone marrow aspirates may show monoclonal plasmacytosis.
- Electron Microscopy (Definitive Diagnosis): Shows non-branching fibrils of indefinite length with a diameter of approximately 7.5 to 10 nm.
- Common sites for biopsy in systemic amyloidosis are the kidney, rectum, or gingival tissues.
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Immunocyte-associated amyloidosis: Serum and urine protein electrophoresis and immunoelectrophoresis should be performed.
Special Stains for Amyloid
-
Congo Red: Most widely used specific stain for amyloid.
- Under a light microscope, Congo red stains amyloid red.
- Under polarized light, Congo red-stained amyloid exhibits apple-green birefringence.
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Thioflavin ‘T’ and ‘S’: Produce secondary immunofluorescence under ultraviolet light.
- Thioflavin T is useful for demonstrating the juxtaglomerular apparatus of the kidney.
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Metachromatic stains: Crystal violet and methyl violet stain amyloid a rose pink color.
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Amyloid is PAS positive (periodic acid-Schiff stain).
Morphology
Main Organs Involved
- Primary amyloidosis: Heart, GI tract, respiratory tract, peripheral nerves, skin, and tongue.
- Secondary amyloidosis: Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid.
Gross Examination
- May not be apparent grossly.
- If large amounts accumulate, affected organs are enlarged, firm, and have a waxy appearance.
- Cut Surface: If amyloid deposits are large, painting the cut surface with iodine yields a yellow color, which turns blue-violet after applying sulfuric acid (acidifies iodine).
Microscopy
- Amyloid deposits are always extracellular.
- Appear as an amorphous, eosinophilic, hyaline, glassy substance.
- Many other substances (e.g., collagen, fibrin) also stain eosinophilic with hematoxylin and eosin, so differentiation with special stains is necessary.
Kidney
- Amyloid deposits in glomeruli (in the basement membrane of capillary loops) and blood vessel walls.
Spleen
- Amyloid causes marked splenomegaly and deposits in splenic sinuses and splenic follicles.
Liver
- Amyloid causes marked hepatomegaly and deposits in blood vessel walls and sinusoids.
Heart
- Amyloid leads to heart enlargement in elderly individuals and deposits between myocardial fibers.
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