Chapter 33: Amyloidosis

November 15, 2020Elementary Immunology

AMYLOIDOSIS

Definition:

Amyloidosis is a generic term that refers to a group of diverse extracellular proteins, which are insoluble fibrillar proteins, arranging themselves as non-branching β-pleated sheets that are resistant to proteolysis and phagocytosis.

These have:

1. Common morphologic properties.
2. Affinity for specific dye-congo-red.
3. Characteristic appearance under polarized light.

With Light Microscope and Haematoxylin/Eosine stain

Amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance that with progressive accumulation, encroaching on and producing pressure atrophies of the adjacent cells.

Amyloidosis

Amyloidosis is not a single disease. It is a group of diseases having in common the deposition of similar appearing proteins.

Fig 176: Physical Structure of Amyloid Material

E/M shows non-branching fibrils of indefinite length and diameter approximately 7.5-10nm.

X-ray-crystallography and infrared spectroscopy show characteristic β-pleated sheets.

Chemical Nature

• 95% of the amyloid material consists of fibril proteins.
• 5% P-component and other glycoproteins.

Classification

There are 15 biochemically distinct forms but the most common are the following.

1. AL (Amyloid Light Chain).
2. AA (Amyloid associated non-Ig-proteins which forms in the liver).
3. AB-Found in Alzheimer’s disease.

Classification by Type of Proteins

1. AL Amyloid: This type consists of the usually variable region of the light chain of immunoglobulin. It is mostly derived from l (Lambda) and rarely from K (Kappa) chains. This condition is associated with:-
   1. Multiple myeloma (10-15% of myeloma patients develop AL amyloid).
   2. B-cell lymphoma.
2. AA Amyloid: It is derived from acute-phase proteins and commonly found in patients with chronic inflammatory diseases, neoplastic diseases, and hereditary disorders which leads to so-called secondary amyloidosis.

Clinical Classification

This is based on clinical presentation. These are of following types.

1. Primary Amyloidosis

This is the most common type of amyloidosis. It appears without any preceding disease. In 1/3 cases it is due to plasma cell neoplasm. Also seen in B-cell lymphoma.  Light chains of immunoglobulin molecules are excessively produced by neoplastic plasma cells either as an idiopathic disease or as part of Frank multiple myeloma.

2. Secondary Amyloidosis

There is the deposition of serum protein (serum amyloid A or AA). It is due to previous chronic inflammatory diseases like rheumatoid arthritis, system lupus erythematosus, ankylosing spondylitis. Other chronic infectious diseases are:- Tuberculosis, lung abscess, and chronic osteomyelitis.

This may also be seen in Hodgkin’s Lymphoma and Renal cell carcinoma.

3. Isolated or Localized Amyloidosis

It tends to involve a single organ or tissue. e.g. in Alzheimer’s disease, amyloid is only in the brain and its blood vessels. This is β-amyloid protein.

1. In Down Syndrome, this may be seen in features like Alzheimer’s in all patients but the age is 35 years.
2. In Diabetes Mellitus, Amyloid deposits are seen in islets cells of Langerhan’s. It is derived from peptide related to a variant of calcitonin.
3. In Senile Cardiac Amyloidosis, This may occur in men after the age of 70 years.

Pathogenesis

Amyloidosis pathogenesis may be simply by some stimuli which give rise to insoluble fibrils or unknown is due to the chronic inflammatory process.

Fig 177: Pathogenesis of Amyloidosis

Clinical Features

1. There may be clinical manifestations and amyloidosis ultimately leads to death.
2. Signs and symptoms depend upon the involvement of organs.
3. Non-specific S/S are—weakness, weight loss, light-headedness, or syncope.
4. Specific S/S appears late and these are related to the organ involved e.g. Heart, GIT, or Renal system.
5. There may be hepatomegaly and splenomegaly.
6. Renal involvement is a life-threatening and dominant feature in systemic amyloidosis.

Consequences of Amyloidosis

Amyloid fibrils when first deposited are usually in close association with subendothelial basement. The amyloid deposit occurs between parenchymal cells and then around blood vessels supply. Extensions of these deposits eventually entrap the parenchymal cells and interfere with their nutrition and strangulate those cells. Ultimately, atrophy takes place.

Commonly Affected Organs

Kidney

This may occur in-patient with multiple myeloma and chronic long-standing inflammatory disorders. Clinically these patients develop nephrotic syndrome. Because of progressive glomerular obliteration, ultimately renal failure takes place.

Heart

This is usually seen in the systemic form of amyloidosis. There is entrapment of the conduction system, which leads to arrhythmias and sudden death.

Gastrointestinal Tract

Amyloidosis involves ganglia, smooth muscles, and vasculature. Clinically patients will complain of either constipation or diarrhea. Occasionally there may be signs of malabsorption.

Endocrines

The localized form of amyloidosis may be found in certain endocrines tumors like:-

1. Medullary carcinoma of the thyroid.
2. Islets tumor of the pancreas.
3. Undifferentiated carcinoma of the stomach.

Diagnosis

1. Rectal biopsy, which will be positive for congo-red stain. Other sites are gingival or kidney.
2. Up to 80% of primary amyloidosis patients may have low-level paraproteins in the serum or urine.

Treatment

1. The reversal of the deposition of amyloid is difficult.
2. Management should stop further deposition which may be achieved by Melphalan and corticosteroids.
3. In the case of secondary amyloidosis, the underlying cause may be treated.

Prognosis

In the systemic form of amyloidosis, the patient course is usually unremitting and ultimately fatal.

Patients with multiple myeloma and AL amyloidosis generally die within 1-2 years.

Patients with AA amyloidosis may die within 5 years due to cardiac or renal failure.