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Questions and Answers
What is the location of amyloid deposition in the kidneys?
What is the location of amyloid deposition in the kidneys?
What macroscopic feature characterizes an organ affected by amyloidosis?
What macroscopic feature characterizes an organ affected by amyloidosis?
In which organ does amyloid deposition lead to enlargement and cause deposition in splenic sinuses?
In which organ does amyloid deposition lead to enlargement and cause deposition in splenic sinuses?
What specific staining technique is used to differentiate amyloid deposits?
What specific staining technique is used to differentiate amyloid deposits?
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Where is amyloid deposited in the heart, particularly affecting the elderly?
Where is amyloid deposited in the heart, particularly affecting the elderly?
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What component synthesizes the Amyloid P in the liver?
What component synthesizes the Amyloid P in the liver?
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In which type of amyloidosis is amyloid deposition primarily AL type?
In which type of amyloidosis is amyloid deposition primarily AL type?
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What is a common cause of secondary amyloidosis?
What is a common cause of secondary amyloidosis?
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Which organ is most commonly associated with primary amyloidosis?
Which organ is most commonly associated with primary amyloidosis?
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What diagnostic method is most specific for detecting amyloid deposits?
What diagnostic method is most specific for detecting amyloid deposits?
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What condition is characterized by amyloid deposition due to recurrent inflammation?
What condition is characterized by amyloid deposition due to recurrent inflammation?
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Which type of amyloidosis is commonly found in elderly patients?
Which type of amyloidosis is commonly found in elderly patients?
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What is the main reason for hemodialysis-associated amyloidosis?
What is the main reason for hemodialysis-associated amyloidosis?
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Which of the following statements is true regarding amyloid deposits?
Which of the following statements is true regarding amyloid deposits?
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What type of tissue is the best site for taking a biopsy when suspecting systemic amyloidosis?
What type of tissue is the best site for taking a biopsy when suspecting systemic amyloidosis?
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Which protein is associated with the mutant TTR gene in familial amyloidotic neuropathies?
Which protein is associated with the mutant TTR gene in familial amyloidotic neuropathies?
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Which clinical feature may indicate renal involvement in amyloidosis?
Which clinical feature may indicate renal involvement in amyloidosis?
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What is the role of Apolipoprotein E (apoE) in amyloidosis?
What is the role of Apolipoprotein E (apoE) in amyloidosis?
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Under polarized light, amyloid appears with which characteristic color when stained with Congo red?
Under polarized light, amyloid appears with which characteristic color when stained with Congo red?
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What is the main component of amyloid material?
What is the main component of amyloid material?
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Which type of amyloid protein is produced by plasma cells?
Which type of amyloid protein is produced by plasma cells?
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Which cytokines are involved in the increased synthesis of serum amyloid-associated protein (SAA)?
Which cytokines are involved in the increased synthesis of serum amyloid-associated protein (SAA)?
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What is the diameter of amyloid fibrils as observed under an electron microscope?
What is the diameter of amyloid fibrils as observed under an electron microscope?
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What condition is associated with amyloid light chain (AL) protein?
What condition is associated with amyloid light chain (AL) protein?
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Which protein is derived from the serum amyloid-associated (SAA) protein?
Which protein is derived from the serum amyloid-associated (SAA) protein?
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Which of the following is a minor form of amyloid protein?
Which of the following is a minor form of amyloid protein?
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What characterizes the structure of amyloid fibrils?
What characterizes the structure of amyloid fibrils?
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Study Notes
Amyloidosis: Definition and Pathogenesis
- Amyloidosis encompasses a spectrum of diseases characterized by the accumulation of amyloid protein in the extracellular space of various tissues and organs.
- Amyloid consists of insoluble, linear, rigid, and non-branching fibrils with a diameter of approximately 7.5 to 10 nm.
- Amyloid formation occurs due to either the overproduction of normal proteins or the production of abnormal, mutant protein forms.
Amyloid Composition
- Approximately 95% of the amyloid material is composed of fibril proteins.
- The remaining 5% comprises non-fibrillar components, including proteoglycans, glycosaminoglycans, serum P components, and others.
Fibril Proteins
- Major Forms: AL and AA
- AL (Amyloid Light Chain): Consists of complete immunoglobulin (Ig) light chains or amino-terminal fragments of light chains. It is produced by plasma cells and is associated with monoclonal B cell proliferation, such as plasma cell tumors. AL is found in primary systemic amyloidosis.
- AA (Amyloid-Associated): Non-immunoglobulin protein derived from a larger precursor, SAA (serum amyloid-associated) protein, synthesized by the liver. Increased SAA protein synthesis occurs during inflammation under the influence of cytokines like IL-6 and IL-1. AA amyloid is associated with chronic inflammation, known as secondary amyloidosis.
- Minor Forms:
- Transthyretin (TTR): A normal serum protein that transports thyroxine and retinol. Mutations in the gene encoding TTR can alter its structure, leading to misfolding and amyloid formation. TTR amyloid is found in familial amyloid polyneuropathies.
- Amyloid B 2-microglobulin (AB2M): Found in amyloidosis of patients on long-term hemodialysis.
- Amyloid B-peptide (AB): Distinct from AB2M, and is deposited in cerebral amyloid angiopathy and neurofibrillary tangles in Alzheimer’s disease. AB is derived from amyloid precursor protein (APP).
- Endocrine Amyloid: Derived from hormone precursor proteins like pro-calcitonin (ACal), islet amyloid polypeptide (AIAPP, amylin), pro-insulin (AIns), prolactin (APro), and others.
- Amyloid of prion protein (APrP): Derived from precursor prion protein, a plasma membrane glycoprotein. Prion proteins are proteinaceous infectious particles lacking RNA or DNA.
Non-fibrillar Components
- Roughly 5% of the amyloid material.
- Examples:
- Amyloid P (AP) component: Synthesized in the liver and present in all types of amyloid. Derived from circulating serum amyloid P-component, a glycoprotein resembling 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.
Classification of Amyloidosis
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Distribution:
- Generalized (Systemic): Amyloid deposits at distant sites from the producing cells.
- Localized: Amyloid deposits near cells producing it.
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Etiology:
- Inherited (Primary): Genetic mutations.
- Acquired (Secondary): Caused by external factors.
- Type of Amyloid Fibril Protein: Refer to the previous section on fibril proteins.
Systemic Amyloidosis: Subtypes
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A) Primary Amyloidosis:
- Associated with blood dyscrasias, particularly multiple myeloma (a malignant tumor of plasma cells).
- AL type amyloid deposition.
- Malignant plasma cells secrete excessive amounts of immunoglobulin light chains, known as Bence Jones protein, which can be found in serum and urine.
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B) Secondary Amyloidosis:
- Systemic AA type amyloid deposition.
- Associated with:
- Infections, e.g., tuberculosis.
- Non-infectious chronic inflammatory processes, e.g., bronchiectasis, chronic osteomyelitis, rheumatoid arthritis, inflammatory bowel diseases.
- Chronic inflammation may lead to the activation of macrophages, which secrete IL-1 and IL-6, stimulating the liver to produce serum amyloid-associated protein (SAA). SAA then forms AA amyloid.
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C) Senile Systemic Amyloidosis:
- Characterized by systemic amyloid deposition in elderly, usually between 70 and 80 years old.
- The amyloid is composed of the normal TTR molecule.
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D) Hemodialysis-Associated Amyloidosis:
- Occurs in patients with chronic renal failure on long-term hemodialysis who have high serum levels of B2 microglobulin. This protein cannot be filtered through dialysis membranes and is deposited as amyloid.
Hereditary or Familial Amyloidosis
- Heterogeneous and rare group of disorders, often occurring in specific geographic areas.
- Examples:
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Familial Mediterranean Fever:
- Autosomal recessive disorder.
- Characterized by recurrent attacks of fever accompanied by inflammation of serosal surfaces (peritoneum, pleura, and synovial membrane).
- The gene mutation affects a protein called pyrin, which regulates inflammatory reactions. Mutations lead to high levels of pro-inflammatory cytokines, like IL-1.
- AA type amyloid fibril proteins, likely due to recurrent bouts of inflammation.
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Familial Amyloidotic Neuropathies:
- Characterized by amyloid deposition in peripheral and autonomic nerves.
- Fibrils are composed of mutant TTR proteins.
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Familial Mediterranean Fever:
Localized Amyloidosis
- Amyloid deposits are confined to a single organ or tissue without involvement of other sites, forming nodules.
- Examples: lung, larynx, skin, tongue.
- AL type amyloid deposition.
- Some cases are associated with endocrine tumors (endocrine amyloid), such as medullary carcinoma of the thyroid and carcinoma of the stomach.
Clinical Features
- Initial symptoms may be nonspecific, such as weakness and weight loss.
- Organ-specific symptoms appear later:
- Renal Involvement: Can lead to proteinuria, potentially massive enough to cause nephrotic syndrome. Advanced cases result in glomerular obliteration, causing renal failure and uremia.
- Cardiac Amyloidosis: May manifest as congestive heart failure, conduction disturbances, and arrhythmias.
- Gastrointestinal Amyloidosis: May be asymptomatic or present as malabsorption, diarrhea, and digestive disturbances.
Diagnosis
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Biopsy: Histologic examination of tissue samples to demonstrate amyloid deposits. Most common biopsy sites for systemic amyloidosis: kidney, rectum, or gingival tissues. The rectum is often considered the best biopsy site.
- Congo Red Stain: Widely used specific stain for amyloid. Under light microscopy, amyloid appears red, but under polarized light, the Congo red stained amyloid exhibits apple-green birefringence.
- Thioflavin ‘T’ and ‘S’: Produce secondary immunofluorescence with ultraviolet light. Thioflavin T is particularly useful for demonstrating the juxtaglomerular apparatus of the kidney.
- Metachromatic Stains: Crystal violet and methyl violet give a rose pink appearance to amyloid.
- PAS Staining: Amyloid is PAS-positive.
- Electron Microscopy: Confirms the diagnosis by revealing nonbranching fibrils of indefinite length with a diameter of approximately 7.5 to 10 nm.
- Immunocyte-Associated Amyloidosis: Serum and urine protein electrophoresis and immunoelectrophoresis are employed to detect monoclonal proteins.
Morphology
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Main Organs Involved:
- Primary amyloidosis: Heart, gastrointestinal tract, respiratory tract, peripheral nerves, skin, and tongue.
- Secondary amyloidosis: Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid.
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Gross Appearance:
- Amyloid deposits may be difficult to discern grossly.
- When significant deposits are present, affected organs can be enlarged, firm, and have a waxy appearance.
- Cut Surface: Large amyloid deposits can be stained with iodine, producing a yellow color, which turns blue-violet after applying sulfuric acid.
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Microscopy:
- Amyloid deposits are always extracellular.
- Appear as an amorphous, eosinophilic, hyaline, glassy substance.
- Requires special staining to differentiate amyloid from other eosinophilic hyaline deposits.
- In Kidney: Amyloid deposits in the glomeruli (basement membrane of capillary loops) and walls of blood vessels.
- In Spleen: Massive splenic enlargement caused by amyloid deposition in splenic sinuses and follicles.
- In Liver: Leads to marked liver enlargement with amyloid deposition in the walls of blood vessels and sinusoids.
- In Heart: Amyloid leads to cardiac enlargement, particularly in the elderly, and is deposited between myocardial fibers.
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Description
This quiz delves into amyloidosis, a group of diseases caused by amyloid protein accumulation in various tissues and organs. Learn about the formation of amyloid, its composition, and the major fibril proteins involved, such as AL and AA. Test your understanding of this complex pathological condition.
