Amyloidosis is a group of diseases having in common the deposition of similar-appearing proteins. Amyloid is a pathologic proteinaceous substance, deposited between cells in various tissues and organs of body in a wide variety of clinical settings.
Chemical Nature of Amyloid: Of 15 bio-chemically distinct forms of amyloid proteins, Three most common are :(1) AL (amyloid light chain) protein: derived from plasma cells and contains immunoglobulin light chains.(2) AA (amyloid-associated) protein: non immunoglobulin protein synthesized by liver.(3) β-amyloid protein (Aβ) : derived from a transmembrane glycoprotein.
Several other biochemically distinct proteins have been found in amyloid deposits:o Transthyretin (TTR) is a normal serum protein that binds and transports thyroxine and retinol, hence the name trans-thy-retin.o β2-microglobulin (Aβ2m) a component of MHC class I molecules.o Calcitonin: derived from C-cell ( parafollicular cell ) of thyroid gland.
Classification of Amyloidosis: Systemic (Generalized) Amyloidosis: primary amyloidosis:o Immunocyte dyscrasias with amyloidosis: as in Multiple myeloma and other monoclonal B-cell proliferations [ AL protein ]. secondary amyloidosis:o Chronic inflammatory conditions such as T.B, bronchiectasis, and osteomyelitis [ AA protein ].o Hemodialysis-associated amyloidosis in Chronic renal failure[ β2-microglobulin( Aβ2m )].
Pathogenesis: Amyloidosis results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function. Misfolded proteins are often unstable. The proteins that form amyloid fall into two general categories: (1) normal proteins that have an inherent tendency to fold improperly, and do so when they are produced in increased amounts.
(2) mutant proteins that are structurally unstable and prone to misfolding and subsequent aggregation. Normally, misfolded proteins are degraded intracellularly in proteasomes ; or extracellularly by macrophages. It appears that in amyloidosis, these quality control mechanisms fail, so that, too much of a misfolded protein accumulates outside cells.
Morphology: Macroscopically : the affected organs are often enlarged and firm and have a waxy appearance. Microscopically:o The most commonly used staining technique employs the dye Congo red, which under ordinary light imparts a pink or red color to amyloid deposits.o Under polarized light, the Congo red-stained amyloid shows a green birefringence.o By electron microscopy, amyloid is made up of nonbranching fibrils ( β-pleated sheet ).
Specific Organs- Morphology:Kidney: renal amyloidosis is the major cause of death. Histologically:- the amyloid is deposited primarily in glomeruli, but interstitial peritubular tissue, arteries, and arterioles are also affected.
Spleen:o Amyloidosis of spleen may be inapparent grossly or may cause moderate to marked splenomegaly .o two patterns of deposition are seen:• the deposit is largely limited to splenic follicles, producing tapioca-like granules on gross inspection, designated as sago spleen.• in red pulp the amyloid appears to spare follicles and instead involves walls of splenic sinuses.o Fusion of early deposits gives rise to large, maplike areas of amyloidosis, designated as lardaceous spleen.
Liver:o The deposits may be in apparent grossly or may cause moderate to marked hepatomegaly.o The amyloid appears first in space of Disse and then progressively encroaches on adjacent hepatic parenchymal cells and sinusoids.o In time, pressure atrophy, and disappearance of hepatocytes occur, causing total replacement of large areas of liver parenchyma.o Normal liver function is usually preserved despite sometimes quite severe involvement of liver.
Heart:o the deposits begin in focal subendocardial accumulations and within myocardium between the muscle fibers.o Expansion of these myocardial deposits eventually causes pressure atrophy of myocardial fibers Other Organs:o Nodular depositions in tongue may cause macroglossia.o Depositions of amyloid in carpal ligament of wrist, resulting in compression of median nerve (carpal tunnel syndrome).
Clinical Correlation: Clinical manifestations at first are nonspecific, such as weakness, weight loss, light headache, or syncope. more specific findings appear later and relate to renal, cardiac, and gastrointestinal involvement. Renal involvement :o proteinuria and is important cause of nephrotic syndrome .o Progressive obliteration of glomeruli in advanced cases ultimately leads to renal failure and uremia.
Cardiac amyloidosis :o congestive heart failure.o conduction disturbances and arrhythmias, which may be fatal.o Occasionally restrictive cardiomyopathy , and chronic constrictive pericarditis . Gastrointestinal amyloidosis:o may be asymptomatic.o Amyloidosis of tongue may cause sufficient enlargement and inelasticity to hamper speech and swallowing.o Depositions in stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion.
Diagnosis of amyloidosis: depends on demonstration of amyloid deposits in tissues. The most common sites biopsied are kidney, rectal or gingival tissues in patients suspected of having systemic amyloidosis. In suspected cases of immunocyte-associated amyloidosis:o serum and urine protein electrophoresis , and immunoelectrophoresis should be performed.o Bone marrow aspirates in such cases often show plasmacytosis, even in absence of overt multiple myeloma.
prognosis: for patients with generalized amyloidosis is poor. Those with immunocyte-derived amyloidosis (not including multiple myeloma) have a median survival of 2 years after diagnosis. Patients with myeloma-associated amyloidosis have a poorer prognosis. The outlook for patients with reactive systemic amyloidosis is some what better and depends on control of underlying condition. New therapeutic strategies aimed at correcting protein misfolding and inhibiting fibrillogenesis are being developed.