Amyloidosis

Sample for Diagnosis

 Tissue biopsies from various sites are recommended.

1. Gingiva: The gingival biopsy is positive in one half to two-thirds of the cases.
2. Rectum: The rectal biopsy is also positive in two-third of the cases.
3. Kidney: Needle biopsy of the kidney is needed when gingival and rectal biopsies are not helpful.
4. Skin: The skin biopsy may also be the site for amyloidosis diagnosis.
5. Another site depends upon the involvement of other organs like GIT, spleen, and respiratory tracts.

Pathophysiology:

1. Amyloid is a Greek word meaning resembling starch.
2. Amyloidosis is a rare disease that occurs when a substance called amyloid (folded protein) builds up in various organs.
   1. Amyloid is a pathological extracellular deposit that appears structureless and translucent and it stains with iodine and various dyes.
   2. Its affinity with congo red is the basis of its definition and identification in the biopsy material.
   3. Under polarized light amyloid with congo red shows apple-green fluorescence.
3. Amyloid exerts pressure on the vital organs and leads to death.
4.  Amyloid is an abnormal protein that is usually produced in bone marrow, are insoluble proteins and can be deposited in any tissue or organ.
   1. Amyloidosis is usually seen in the heart, liver, spleen, kidney, nervous system, and gastrointestinal system.
5. Amyloid is an extracellular deposit of the amyloid protein.
   1. Hematoxylin and eosine stains show amyloid as amorphous, eosinophilic, hyaline extracellular substance.
   2. It encroaches on the adjacent cells and leads to atrophy of the surrounding cells.
   3. This is not a single disease rather it is a group of diseases sharing deposition of similar appearing proteins.
6. Biochemistry of the amyloid:
   1. Amyloid is insoluble protein, resistant to the normal proteolysis due to its β- conformation.
   2. This above feature is common to all types of amyloid whatever is their composition.
   3. Amyloid fibrils may have multiple soluble plasma proteins precursors, modified by proteolysis to make them insoluble.
   4. The end result of this insoluble amyloid is the disease called amyloidosis.
   5. This deposit may be local or systemic.
      1. This amyloid material exerts local pressure and the end result is the death of the tissue.

Structure of the amyloid:

1. By electron microscopy, it is nonbranching fibrils 7.5 to  10 nm in width.
2. Under the Electron microscope consists of:
   1. Two fibrillary components with characteristic periodicity.
   2. One rod-like structure P-component which glycoprotein on their head.
   3. This has a hollow core and is a pentamer.

3. These fibrillary components are crossed β-pleated sheets, seen by X-Ray crystallography.
4. Any fibrillar proteins deposited in the tissue which looks like β-pleated sheets are amyloid.
5. 95% of the amyloid is fibril proteins and the rest 5% consists of P components or glycoproteins.

Chemical nature of the amyloid:

1. There are roughly 15 amyloid proteins and three of these are very common.
   1. Amyloid light chain (AL). These are derived from the plasma cells and consists of immunoglobulin light chains.
      1. This may be light chain κ or λ.
      2. This is seen in plasma cell neoplasm, lymphomas, cardiomyopathy, macroglossia, and hepatosplenomegaly.
   2. Amyloid-associated amyloid (AA). This is non-immunoglobulin proteins synthesized by the liver.
      1. This also called serum amyloid-A protein (SAA).
      2. This is a secondary amyloidosis. This is seen in:
         1. Chronic diseases like tuberculosis, bronchiectasis, Crohn’s disease,  nephrotic syndrome, cardiomyopathy, and rheumatoid arthritis.
   3. αβ amyloid is β-precursor protein and found in:
      1. Patients with Alzheimer’s disease.
      2. Type 2 diabetes.
   4. β₂  Microglobulin amyloid  is β2  Microglobulin and found in:
      1. Renal failure.
      2. Musculoskeletal diseases.
      3. Long term hemodialysis.
   5. ATTR amyloid is transthyretin. It is found in:
      1. Neuropathy.
      2. Cardiomyopathy.
      3. Senile amyloidosis with cardiomyopathy.

Types of Amyloidosis:

1. 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.
   1. Amyloidosis associated with multiple myeloma.
   2. These two types associated with the increasing number of plasma cells (Plasmacytosis).
   3. There is the monoclonal proliferation of the cells giving two identical light chains known as AL amyloid.

3. Secondary Amyloidosis is a result of a chronic illness like tuberculosis, osteomyelitis or other chronic inflammatory diseases like rheumatoid arthritis and ankylosing spondylitis.
   1. This is called as secondary amyloidosis or AA amyloid.
   2. Rheumatoid arthritis has an incidence of 20%.
   3. Deposits of AA amyloid most frequently occur in the kidney, liver, and spleen.
   4. There may be nephrotic syndrome and hepatosplenomegaly.
4. Aging: Amyloidosis associated with the aging process.
   1. This also called senile amyloidosis and most often the heart is involved called senile cardiac amyloidosis.
5. Familial Amyloidosis.

Classification of Amyloidosis:

1. Amyloidosis may be:
   1. Generalized or systemic: Multiple organs are involved.
      1. Primary amyloidosis when there is a disturbance of the immune system.
         1. Seen in multiple myeloma and monoclonal B-cell proliferation.
      2. Secondary amyloidosis when the cause is a chronic inflammatory disease.
         1. Reactive systemic amyloidosis.
   2. Localized: In this type, only one organ is involved like amyloidosis of heart.
      1. Senile cereberal changes seen in Alzheimer’s disease.
      2. In medullary carcinoma of the thyroid (endocrine).
      3. Islets of Langerhans (endocrine).
      4. Isolated atrial amyloidosis.
   3. Hereditary or familial amyloidosis is a separate group with a different pattern of organ involvement.
      1. Familial Mediterranian fever.
      2. Familial amyloidotic neuropathies.
   4. 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.
      1. Nodular or infiltrative amyloid deposits may be seen in the skin, lungs, and trachea.
      2. May be seen in long-standing diabetes mellitus in the pancreas.
      3. May be seen in the thyroid in case of medullary carcinoma.
         1. These forms are asymptomatic except the heart.

The sign and symptoms:

1. Except for the familial type of amyloidosis, it is seen in older patients with an average age of 60 years.
2. These depend upon the organ involved.
3. There are severe fatigue and weakness.
4. There is shortness of breath.
5. There may be diarrhea with blood and sometimes there is constipation.
6. There may be swelling of ankles and legs.
7. The skin may show thickening or easy bruising and patches around the eyes.
8. The most commonly involved organs are Kidney and heart.
9. There may be an irregular heartbeat.
10. The patient may develop difficulty in swallowing.
11. Kidneys involvement leads to nephrotic syndrome. There may or may not be raised creatinine and blood urea.
12. 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:

1. Age, the most common age group involved are 50 or older people with an exception for the younger age group.
2. Family history, some of the amyloidosis are hereditary.
3. Sex, the majority of the patients are male.
4. Dialysis of the patient also leads to amyloidosis.
5. Chronic diseases predispose to amyloidosis.

Causes of the amyloidosis:

1. Leprosy in 1/3 of the cases.
2. Chronic infections like osteomyelitis, tuberculosis. etc.
3. Multiple myelomas.
4. 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:

1. There is no definite treatment or cure for amyloidosis.
2. But treatment can limit the production of amyloid protein.

Prognosis

1. It depends upon the type of amyloidosis and the organ involved.
2. Microscopic and focal deposits in older people are of no clinical significance.
3. Widespread deposits are progressive and fatal.
4. AL Amyloid patients with cardiac involvement have a worse prognosis and in untreated cases, is less than the survival is one year.
5. AA amyloid patients survive 2 to 4 years.
6. ATTR amyloid patients survive for 15 years.
7. Treatment is aimed at:
   1. Reducing the supply of precursor protein.
   2. Treat the bleeding problem.
   3. Increase the motility.

 

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