1. Amyloidosis

2. AMYLOIDOSIS
Amyloid is a pathologic proteinaceous substance, deposited between cells in various tissues and organs of the body in a wide variety of clinical settings.
Amyloidosis is not a single disease; rather it is a group of diseases having in common the deposition of similar-appearing proteins.

3. Amyloid refers to a group of diverse extracellular protein deposits that have
(1) common morphologic properties.
(2) affinities for specific dyes.
(3) when stained, a characteristic appearance under polarized light.
The symptomatology of amyloidosis is governed by both the underlying disease and the type and organ locations of the protein deposited.

4. AMYLOIDOSIS
It is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise.
These abnormal fibrils are produced by the aggregation of misfolded proteins (which are soluble in their normal folded configuration).

5. Constituents of Amyloid
Amyloid deposits are composed of two classes of constituents:
A DISEASE-SPECIFIC FIBRILLOGENIC PROTEIN:
The nature of this protein varies with the underlying disease. The tertiary structure of the protein and the manner in which it interacts with other molecules are responsible for the characteristics of amyloid. The specific fibrillogenic protein in various types of amyloid is now the determining factor in the classification of amyloid.

6. 2. A SET OF COMMON COMPONENTS FOUND IN ALL AMYLOIDS:
The amyloid P component (AP) is a pentagonalprotein that is present in all types of amyloid. AP is identical with a normal circulating serum protein, termed serum amyloid P (SAP). SAP is also a structural component of normal basement membranes.
Other molecular building blocks of basement membranes are present in amyloid and include laminin, collagen type IV, and the proteoglycan perlecan. Heparan sulfate, the glycosaminoglycan side chain of perlecan is also crucial in altering the conformation of the disease-specific fibrillogenic proteins.
Apolipoprotein E is a constituent of high-density lipoproteins and normally plays a role in cholesterol transport.

7. Chemical Nature of Amyloid
- Approximately 95% of the amyloid material consists of fibril proteins
The remaining 5% is P component and other glycoproteins.

8. Physical Nature of Amyloid
By electron microscopy, amyloid is seen to be made up largely of nonbranching fibrils of indefinite length.
This structure is identical in all types of amyloidosis.
The fibers have characteristic cross-β-pleated sheets and are responsible for the distinctive staining and birefringence of Congo red-stained amyloid.

9. Amyloidosis, Most common Forms :
AL (amyloid light chain) is derived from plasma cells and contains immunoglobulin light chains
AA (amyloid-associated) is a unique nonimmunoglobulin protein synthesized by the liver
Aβ amyloid is found in the cerebral lesion of Alzheimer disease

10. Other biochemical forms of Amyloid
Transthyretin (TTR): is deposited familial amyloid polyneuropathies and in the heart of aged individuals (senile systemic amyloidosis).

11. Classification of Amyloidosis.
Amyloid may be classified based on its constituent chemical fibrils into categories such as AL, AA, and ATTR (as described in the previous slides)
Or it can be divided into :
Systemic, (generalized) pattern is subclassified into:
primary amyloidosis, when associated with B- cell dyscrasias
secondary amyloidosis, when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process.
Hereditary or familial amyloidosis constitutes a separate group.
Localized

12. Immunocyte Dyscrasias with Amyloidosis (Primary Amyloidosis)
Usually systemic and is of AL type.
Is the most common form of amyloidosis.
The malignant B cells characteristically synthesize abnormal amounts of a single specific immunoglobulin (monoclonal gammopathy).
primary amyloidosis is an early sign of plasma cell neoplasia, such as multiple myeloma or other B-cell lymphomas.

13. Reactive/ Secondary Systemic Amyloidosis
The amyloid deposition is systemic and is composed of AA protein.
It is secondary to an associated inflammatory condition like rheumatoid arthritis, and inflammatory bowel disease. It may also occur in association with tumors, like renal cell carcinoma.
Most other patients with secondary amyloidosis have long-standing inflammatory conditions (e.g., lung abscess, tuberculosis, or osteomyelitis).

14. Amyloid of Aging
Senile systemic amyloidosis: systemic deposition of amyloid in elderly patients (heart) was previously called senile cardiac amyloidosis.
Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias.
The amyloid in this form is composed of the normal TTR molecule.

15. The Incidence of Familial Amyloidoses May Vary with Ethnicity
Several geographical populations display genetically inherited forms of amyloidosis, of which Familial Mediterranean fever (FMF) is prototypical.

17. Pathogenesis
Amyloidosis results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function.

18. Pathogenesis cont.
The proteins that form amyloid fall into two general categories:
(1) normal proteins that have an inherent tendency to fold improperly and form fibrils, and do so when they are produced in increased amounts
(2) mutant proteins that are structurally unstable and prone to misfolding and then form fibrils.

20. Light microscope: amyloid appears as amorphous, eosinophilic, hyaline, extracellular substance that gradually encroaches on and produces pressure atrophy of adjacent cells.
On congo red stain: amyloid gives a pink or red color under ordinary light and an apple green birefringence under polarizing light.

21. Morphology
Primary amyloidosis cannot reliably be distinguished from the secondary amyloidosis but more often it involves the heart, kidney and, gastrointestinal tract, skin and tongue.
Secondary amyloidosis usually involves kidneys, liver, spleen and lymph nodes as well as many other tissues.

22. Morphology cont.
Macroscopically the affected organs are often enlarged and firm and have a waxy appearance.

23. Morphology cont.
Histologic diagnosis of amyloid is based on its characteristic staining with dye Congo red, which under ordinary light imparts a pink or red color to amyloid deposits. Under polarized light, the Congo red-stained amyloid shows a green birefringence

24. Figure 6-55 Amyloidosis of the kidney
Figure 6-55 Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September :13 PM)
© 2005 Elsevier

26. Morphology in Kidney Most common organ involved.
Histologically the amyloid is deposited in the
Glomeruli, with progression there is hyalinization of the glomeruli.
Peritubular region extending into interstitium.
Blood vessels: hyaline thickening of the arteriolar wall and narrowing of lumen, eventually causing ischemia with tubular atrophy and interstitial fibrosis.

28. Morphology in Spleen
May cause splenomegaly. There are two patterns of deposition.
Deposit is in the splenic follicles, producing tapioca-like granules on gross inspection, called sago spleen.
Deposit in splenic sinuses and connective tissue of the red pulp. Fusion of deposits gives rise to large, areas of amyloidosis, designated the lardaceous spleen.
Tapioca: granular preparation of cassava starch

31. Morphology in Liver May cause hepatomegaly.
The amyloid appears first in the space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids.
In time due to pressure atrophy, there disappearance of hepatocytes, causing replacement of large areas of liver by amyloid.

32. Morphology in Heart
May be enlarged and firm. Histologically the deposits are subendocardial and within the myocardium between the muscle fibers.
Expansion of these myocardial deposits eventually causes pressure atrophy of myocardial fibers.
When they are subendocardial, the conduction system may be damaged, causing electrocardiographic abnormalities.

33. Clinical Correlation
. Variable presentation: no clinical manifestations, or it may cause death. .The symptoms depend on the magnitude of the deposits and on the organs affected. . At first nonspecific symptoms such as weakness, weight loss, light-headedness, or syncope. Specific findings appear later and most often relate to renal, cardiac, and gastrointestinal involvement.

34. Clinical Correlation
Renal involvement: proteinuria, can cause of the nephrotic syndrome. Progressive obliteration of glomeruli in advanced cases leads to renal failure and uremia
2) Cardiac amyloidosis: insidious congestive heart failure. The most serious complications are conduction disturbances and arrhythmias, which may prove fatal.

35. Clinical Correlation
3) Gastrointestinal amyloidosis: may be asymptomatic. Amyloidosis of the tongue may cause enlargement and hamper speech and swallowing. Depositions in the stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion.

36. Diagnosis
The diagnosis of amyloidosis depends on demonstration of amyloid deposits in tissues.
The most common sites biopsied are the kidney or rectal or gingival tissues in patients suspected of having systemic amyloidosis.

37. Reversibility of Amyloid
The deposits are NOT irreversible.
Progression of generalised amyloidosis can be delayed or stopped by treatment of the underlying disease.

38. Prevention & Therapy of Amyloid
Prevention & treatment of the underlying diseases
Vaccination against β am. protein in mice diminished senile plaque formation and improved memory.
A β –based experimental therapies based on degrading enzymes.