Amyloidosis

Sample for Diagnosis
Tissue biopsies from various sites are recommended.
- Gingiva: The gingival biopsy is positive in one half to two-thirds of the cases.
- Rectum: The rectal biopsy is also positive in two-third of the cases.
- Kidney: Needle biopsy of the kidney is needed when gingival and rectal biopsies are not helpful.
- Skin: The skin biopsy may also be the site for amyloidosis diagnosis.
- Another site depends upon the involvement of other organs like GIT, spleen, and respiratory tracts.
Pathophysiology:
- Amyloid is a Greek word meaning resembling starch.
- Amyloidosis is a rare disease that occurs when a substance called amyloid (folded protein) builds up in various organs.
- Amyloid is a pathological extracellular deposit that appears structureless and translucent and it stains with iodine and various dyes.
- Its affinity with congo red is the basis of its definition and identification in the biopsy material.
- Under polarized light amyloid with congo red shows apple-green fluorescence.
- Amyloid exerts pressure on the vital organs and leads to death.
- Amyloid is an abnormal protein that is usually produced in bone marrow, are insoluble proteins, and can be deposited in any tissue or organ.
- Amyloidosis is usually seen in the heart, liver, spleen, kidney, nervous system, and gastrointestinal system.
- Amyloid is an extracellular deposit of the amyloid protein.
- Hematoxylin and eosine stains show amyloid as amorphous, eosinophilic, hyaline extracellular substance.
- It encroaches on the adjacent cells and leads to atrophy of the surrounding cells.
- This is not a single disease rather it is a group of diseases sharing deposition of similar appearing proteins.
- Biochemistry of the amyloid:
- Amyloid is an insoluble protein, resistant to the normal proteolysis due to its β- conformation.
- This above feature is common to all types of amyloid whatever is their composition.
- Amyloid fibrils may have multiple soluble plasma proteins precursors, modified by proteolysis to make them insoluble.
- The end result of this insoluble amyloid is the disease called amyloidosis.
- This deposit may be local or systemic.
- This amyloid material exerts local pressure and the end result is the death of the tissue.
Structure of the amyloid:
- By electron microscopy, it is nonbranching fibrils 7.5 to 10 nm in width.
- Under the Electron microscope consists of:
- Two fibrillary components with characteristic periodicity.
- One rod-like structure P-component which glycoprotein on their head.
- This has a hollow core and is a pentamer.
- These fibrillary components are crossed β-pleated sheets, seen by X-Ray crystallography.
- Any fibrillar proteins deposited in the tissue which looks like β-pleated sheets are amyloid.
- 95% of the amyloid is fibril proteins and the rest 5% consists of P components or glycoproteins.
Chemical nature of the amyloid:
- There are roughly 15 amyloid proteins and three of these are very common.
- Amyloid light chain (AL). These are derived from the plasma cells and consists of immunoglobulin light chains.
- This may be light chain κ or λ.
- This is seen in plasma cell neoplasm, lymphomas, cardiomyopathy, macroglossia, and hepatosplenomegaly.
- Amyloid-associated amyloid (AA). This is non-immunoglobulin proteins synthesized by the liver.
- This also called serum amyloid-A protein (SAA).
- This is secondary amyloidosis. This is seen in:
- Chronic diseases like tuberculosis, bronchiectasis, Crohn’s disease, nephrotic syndrome, cardiomyopathy, and rheumatoid arthritis.
- αβ amyloid is a β-precursor protein and found in:
- Patients with Alzheimer’s disease.
- Type 2 diabetes.
- β2 Microglobulin amyloid is β2 Microglobulin and found in:
- Renal failure.
- Musculoskeletal diseases.
- Long term hemodialysis.
- ATTR amyloid is transthyretin. It is found in:
- Neuropathy.
- Cardiomyopathy.
- Senile amyloidosis with cardiomyopathy.
- Amyloid light chain (AL). These are derived from the plasma cells and consists of immunoglobulin light chains.
Types of Amyloidosis:
- Primary Amyloidosis consists of a portion of the light chain so-called an immunoglobulin light chain (AL) amyloidosis. This is produced spontaneously from the plasma cells and this may be seen in the cancer of bone marrow like Multiple myelomas.
- Amyloidosis associated with multiple myeloma.
- These two types associated with the increasing number of plasma cells (Plasmacytosis).
- There is the monoclonal proliferation of the cells giving two identical light chains known as AL amyloid.
- Secondary Amyloidosis is a result of a chronic illness like tuberculosis, osteomyelitis or other chronic inflammatory diseases like rheumatoid arthritis and ankylosing spondylitis.
- This is called as secondary amyloidosis or AA amyloid.
- Rheumatoid arthritis has an incidence of 20%.
- Deposits of AA amyloid most frequently occur in the kidney, liver, and spleen.
- There may be nephrotic syndrome and hepatosplenomegaly.
- Aging: Amyloidosis associated with the aging process.
- This also called senile amyloidosis and most often the heart is involved called senile cardiac amyloidosis.
- Familial Amyloidosis.
Classification of Amyloidosis:
- Amyloidosis may be:
- Generalized or systemic: Multiple organs are involved.
- Primary amyloidosis when there is a disturbance of the immune system.
- Seen in multiple myeloma and monoclonal B-cell proliferation.
- Secondary amyloidosis when the cause is a chronic inflammatory disease.
- Reactive systemic amyloidosis.
- Primary amyloidosis when there is a disturbance of the immune system.
- Localized: In this type, only one organ is involved like amyloidosis of heart.
- Senile cerebral changes were seen in Alzheimer’s disease.
- In medullary carcinoma of the thyroid (endocrine).
- Islets of Langerhans (endocrine).
- Isolated atrial amyloidosis.
- Hereditary or familial amyloidosis is a separate group with a different pattern of organ involvement.
- Familial Mediterranian fever.
- Familial amyloidotic neuropathies.
- Senile systemic amyloidosis. This is most often found in the heart, called senile cardiac amyloid. This may also be seen in the brain and pancreas.
- Nodular or infiltrative amyloid deposits may be seen in the skin, lungs, and trachea.
- May be seen in long-standing diabetes mellitus in the pancreas.
- May be seen in the thyroid in case of medullary carcinoma.
- These forms are asymptomatic except the heart.
- Generalized or systemic: Multiple organs are involved.
The sign and symptoms:
- Except for the familial type of amyloidosis, it is seen in older patients with an average age of 60 years.
- These depend upon the organ involved.
- There are severe fatigue and weakness.
- There is shortness of breath.
- There may be diarrhea with blood and sometimes there is constipation.
- There may be swelling of ankles and legs.
- The skin may show thickening or easy bruising and patches around the eyes.
- The most commonly involved organs are Kidney and heart.
- There may be an irregular heartbeat.
- The patient may develop difficulty in swallowing.
- Kidneys involvement leads to nephrotic syndrome. There may or may not be raised creatinine and blood urea.
- There is the involvement of the kidney in 90 to 96 % of the cases with the amyloid type of AA.
Risk factors leading to amyloidosis:
- Age, the most common age group involved are 50 or older people with an exception for the younger age group.
- Family history, some of the amyloidosis are hereditary.
- Sex, the majority of the patients are male.
- Dialysis of the patient also leads to amyloidosis.
- Chronic diseases predispose to amyloidosis.
Causes of the amyloidosis:
- Leprosy in 1/3 of the cases.
- Chronic infections like osteomyelitis, tuberculosis. etc.
- Multiple myelomas.
- Other malignancies like renal cell carcinoma, and lymphomas.
The complication of amyloidosis:
- Kidney, when involved, will ultimately lead to renal failure.
- Kidney size may be normal or enlarged.
- Amyloid deposits in the glomeruli.
- Amyloidosis is also seen in the interstitium, and in the wall of blood vessels.
- The cardiovascular system leads to heart failure and arrhythmias.
- The heart size may increase from minimum to moderate enlargement.
- Amyloid deposits are found in the myocardium.
- The spleen may be enlarged moderately to a large size.
- Amyloid deposit is limited to splenic follicles and giving sago spleen appearance.
- The liver amyloidosis causes massive enlargement.
- The amyloid deposit first appears in the space of Disse.
- Later on, encroach the adjacent liver parenchyma.
- In late stages involve the sinusoids.
- The Central nervous system leads to various types of complications like diarrhea, constipation, numbness of fingers, and dizziness.
Diagnosis:
- Congo-red test: Congo-red binds the amyloid and gives apple-green fluorescence under the polarized light.
Treatment:
- There is no definite treatment or cure for amyloidosis.
- But treatment can limit the production of amyloid protein.
Prognosis
- It depends upon the type of amyloidosis and the organ involved.
- Microscopic and focal deposits in older people are of no clinical significance.
- Widespread deposits are progressive and fatal.
- AL Amyloid patients with cardiac involvement have a worse prognosis and in untreated cases, is less than the survival is one year.
- AA amyloid patients survive 2 to 4 years.
- ATTR amyloid patients survive for 15 years.
- Treatment is aimed at:
- Reducing the supply of precursor protein.
- Treat the bleeding problem.
- Increase the motility.