Pathophysiology
Summary
Amyloidosis is a complex group of disorders marked by the extracellular deposition of abnormally folded proteins, known as amyloid. These amyloid fibers are uniquely characterized by their misfolded beta-pleated sheet structure, which disrupts normal tissue function through a mass effect. Diagnostic identification relies heavily on Congo red staining. revealing an apple-green birefringence under polarized light—indicative of amyloid fibrils.
AL amyloidosis (primary) originates from fragments of immunoglobulin light chains, and often coexists with multiple myeloma. AL amyloidosis is systemic, with a diverse range of tissue and organ involvement. Renal injury occurs due to amyloid deposition in the glomeruli, leading to nephrotic syndrome. Cardiac manifestations include restrictive cardiomyopathy, as amyloid fibers. Other areas of deposition include the tongue, causing macroglossia, and the wrist, leading to carpal tunnel syndrome. Amyloid can also deposit in joints leading to various forms of arthropathy, and in the nervous system, manifesting as a spectrum of neuropathic symptoms ranging from peripheral neuropathy to autonomic dysfunction. Amyloid deposition can also cause hepatosplenomegaly and an increased susceptibility to bleeding.
Reactive systemic amyloidosis (secondary) often arises secondary to chronic inflammatory conditions, most notably rheumatoid arthritis. It is distinguished by the deposition of AA amyloid, derived from fragments of serum amyloid A, an acute-phase reactant. While it can affect numerous tissues like primary amyloidosis, the kidneys are most commonly impaired in reactive systemic amyloidosis, manifesting as nephrotic syndrome.
Dialysis-related amyloidosis emerges from the accumulation of beta-2 microglobulin, a component of MHC I molecules. Beta-2 microglobulins are not efficiently filter by dialysis, leading to deposits in osteoarticular structures, causing issues like carpal tunnel syndrome in patients on long-term dialysis.
Senile cerebral amyloidosis is closely linked to Alzheimer's disease, characterized by the extracellular deposition of Aβ amyloid in the CNS. This form of amyloid originates from amyloid precursor protein (APP). Cerebral amyloid angiopathy (CAA) can occur when Aβ amyloid accumulates in cerebral blood vessels, rendering them fragile and prone to spontaneous cerebral hemorrhage.
Familial mediterranean fever (FMF) is a heritable form of amyloidosis with autosomal recessive inheritance. A mutation in the PYRIN gene triggers excessive cytokine production and persistent inflammation, culminating in AA amyloid deposition that presents as reactive systemic amyloidosis
Various forms of heritable amyloidosis are triggered by mutations in transthyretin (prealbumin). These mutations can result in conditions like Familial amyloidotic polyneuropathies, where mutated transthyretin forms ATTR amyloid in peripheral and autonomic nerves, and familial amyloid cardiomyopathy, where ATTR deposits in the myocardium.
Lastly, systemic senile amyloidosis occurs due to the aggregation of normal, wild-type transthyretin into ATTR amyloid as a result of aging. This form commonly results in myocardial deposits and restrictive cardiomyopathy.
Lesson Outline
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FAQs
Multiple myeloma is characterized by the proliferation of neoplastic monoclonal plasma cells. This results in the overproduction of immunoglobulins, including light chains. These light chains can misfold and form AL amyloid, leading to the presentation of AL amyloidosis in patients with multiple myeloma.
To diagnose amyloidosis, tissues are stained with Congo Red dye. When these stained tissues are examined under polarized light, amyloid fibrils produce a distinct apple-green birefringence. This characteristic appearance confirms the presence of amyloidosis in the tissue.
AL amyloidosis has widespread effects on the body due to amyloid deposits in various tissues. Commonly, it affects the kidneys, manifesting as enlarged kidneys and nephrotic syndrome. The heart can also be impacted, leading to restrictive cardiomyopathy. Other areas, such as the tongue, wrist, joints, and nervous system, can also be affected, resulting in symptoms like macroglossia, carpal tunnel syndrome, joint arthropathy, and diverse neuropathies.
Reactive systemic amyloidosis often arises secondary to chronic inflammatory conditions, with rheumatoid arthritis being a common precursor. It's marked by the deposition of AA amyloid, which is derived from serum amylase A, an acute phase reactant. While it can affect various tissues, the kidneys are most commonly impacted, often leading to nephrotic syndrome.
Several hereditary amyloidosis forms stem from genetic mutations. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder caused by a PYRIN gene mutation, leading to AA amyloid deposition due to chronic inflammation. Familial Amyloidotic Polyneuropathies and Familial Amyloid Cardiomyopathy result from mutated transthyretin causing ATTR amyloid deposition, affecting nerves and the heart, respectively. Systemic senile amyloidosis, on the other hand, arises from the aging-related aggregation of normal transthyretin into ATTR amyloid, primarily affecting the heart.
