Amyloidosis Dr Hisham Alkhalidi

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.

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).

The fibrillar deposits bind a wide variety of: – Proteoglycans – Glycosaminoglycans – Plasma proteins, notably serum amyloid P component (SAP) - Approximately 95% of the amyloid material consists of fibril proteins -The remaining 5% is P component and other glycoproteins. Chemical Nature of Amyloid

Structure of an amyloid fibril, depicting beta-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis Extra reading: Beta-sheets are he second form of regular secondary structure in proteins consisting of beta strands connected laterally by five or more hydrogen bonds, forming a generally twisted, pleated sheet (the most common form of regular secondary structure in proteins is the alpha helix)

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.

Amyloidosis, Most common Forms : (1)AL (amyloid light chain) is derived from plasma cells and contains immunoglobulin light chains (2)AA (amyloid-associated) is a unique nonimmunoglobulin protein synthesized by the liver (3)Aβ amyloid is found in the cerebral lesion of Alzheimer disease

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

Classification of Amyloidosis Table

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

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).

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.

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.

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

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.

Liver HeartKidny

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.

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.

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

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

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

Morphology in Kidney Most common organ involved. Histologically the amyloid is deposited in the 1)Glomeruli, with progression there is hyalinization of the glomeruli. 2)Peritubular region extending into interstitium. 3)Blood vessels: hyaline thickening of the arteriolar wall and narrowing of lumen, eventually causing ischemia with tubular atrophy and interstitial fibrosis.

Morphology in Spleen May cause splenomegaly. There are two patterns of deposition. 1)Deposit is in the splenic follicles, producing tapioca-like granules on gross inspection, called sago spleen. 2)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

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.

Figure 6-56 Cardiac amyloidosis. The atrophic myocardial fibers are separated by structureless, pink-staining amyloid (arrows). Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 September :13 PM) © 2005 Elsevier

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.

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.

Clinical Correlation 1)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.

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.

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.