Diseases of the Immune System
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Amyloidosis
Amyloidosis 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 or protein fragments.
Pathogenesis of Amyloid Deposition
All amyloid deposits are composed of nonbranching fibrils, each formed of β-sheet
polypeptide chains that are wound together. The dye Congo red binds to these fibrils
and produces a red–green birefringence, which is commonly used to identify
amyloid deposits in tissues.
Amyloidosis results from abnormal folding of proteins, which are deposited as fibrils
in extracellular tissues and disrupt normal function. Normally, misfolded proteins
are degraded intracellularly in proteasomes, or extracellularly by macrophages. It
appears that in amyloidosis, these quality control mechanisms fail, allowing the
misfolded protein to accumulate outside cells.
The diverse conditions that are associated with amyloidosis all are likely to result in
excessive production of proteins that are prone to misfolding. The proteins that form
amyloid fall into two general categories:
(1) normal proteins that have an inherent tendency to fold improperly, associate to
form fibrils, and do so when they are produced in increased amounts
(2) mutant proteins that are prone to misfolding and subsequent aggregation.
Most common types of proteins are:
1. The AL (amyloid light chain) protein is produced by plasma cells and is
made up of immunoglobulin light chains, the deposition of amyloid fibril
protein of the AL type is associated with some form of monoclonal B cell
proliferation.
2. The AA (amyloid-associated) fibril is a unique non-immunoglobulin protein
derived from a larger serum precursor called SAA (serum amyloid-associated)
protein that is synthesized in the liver, under the influence of cytokines that
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are produced during inflammation; thus, long-standing inflammation leads to
elevated SAA levels, and ultimately the AA form of amyloid deposits.
3. Aβ amyloid is found in the cerebral lesions of Alzheimer disease. Aβ is a
peptide that constitutes the core of cerebral plaques and the amyloid deposits
in cerebral blood vessels in this disease.
4. Transthyretin (TTR) is a normal serum protein that binds and transports
thyroxine and retinol, hence the name. TTR is also deposited in the heart of
aged persons (senile systemic amyloidosis); in such cases the protein is
structurally normal, but it accumulates at high concentrations.
Classification of Amyloidosis
Amyloidosis is subdivided into systemic (generalized) and localized (tissuespecific) forms and is further classified on the basis of predisposing conditions.
Systemic amyloidosis is associated with the following conditions:
1. Immunocyte Dyscrasias with Amyloidosis
Amyloid in this category usually is systemic in distribution and is of the AL type. In
some of these cases, there is a readily identifiable monoclonal plasma cell
proliferation; best defined is the occurrence of systemic amyloidosis in 5% to 15%
of patients with multiple myeloma.
The malignant plasma cells characteristically synthesize abnormal amounts of a
single specific immunoglobulin (monoclonal gammopathy), producing an M
(myeloma) protein spike on serum electrophoresis. The great majority of patients
with AL amyloid do not have classic multiple myeloma or any other overt B cell
neoplasm; such cases are nevertheless classified as primary amyloidosis because
their clinical features derive from the effects of amyloid deposition without any other
associated disease.
2. Reactive Systemic Amyloidosis
The amyloid deposits in this pattern are systemic in distribution and are composed
of AA protein. This category was previously referred to as secondary amyloidosis,
because it is secondary to an associated inflammatory condition. Classically,
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tuberculosis, bronchiectasis, chronic osteomyelitis, RA, ankylosing spondylitis,
inflammatory bowel disease.
3. Familial (Hereditary) Amyloidosis
The best-characterized is an autosomal recessive condition called familial
Mediterranean fever. This is a febrile disorder characterized by attacks of fever
accompanied by inflammation of serosal surfaces, including peritoneum, pleura, and
synovial membrane. It is associated with widespread tissue involvement
indistinguishable from reactive systemic amyloidosis. The amyloid fibril proteins
are made up of AA proteins, suggesting that this form of amyloidosis is related to
the recurrent bouts of inflammation that characterize this disease.
Localized Amyloidosis
Sometimes deposition of amyloid is limited to a single organ or tissue without
involvement of any other site in the body. The deposits may produce grossly
detectable nodular masses or be evident only on microscopic examination.
1. Nodular (tumor-forming) deposits of amyloid are most often encountered
in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye.
Frequently, there are infiltrates of lymphocytes and plasma cells in the
periphery of these amyloid masses.
2. Endocrine Amyloid of localized amyloid may be found in certain endocrine
tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the
pancreas, pheochromocytomas, and undifferentiated carcinomas of the
stomach.
3. Amyloid of Aging refers to the systemic deposition of amyloid in elderly
persons (usually in their 70s and 80s). Because of the dominant involvement
and related dysfunction of the heart (typically manifesting as a restrictive
cardiomyopathy and arrhythmias), this form also is called senile cardiac
amyloidosis. The amyloid in this form is composed of normal transthyretin.
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Clinical Course
1. Nonspecific complaints such as weakness, fatigue, and weight loss are the
most common presenting manifestations.
2. Later in the course, amyloidosis tends to manifest in one of several ways: by
renal disease, hepatomegaly, splenomegaly, or cardiac abnormalities.
 Renal involvement giving rise to severe proteinuria (nephrotic
syndrome) often is the major cause of symptoms in reactive systemic
amyloidosis. Progression of the renal disease may lead to renal failure,
which is an important cause of death in amyloidosis.
 The hepatosplenomegaly rarely causes significant clinical dysfunction,
but it may be the presenting finding.
 Cardiac amyloidosis may manifest as conduction disturbances or as
restrictive cardiomyopathy. Cardiac arrhythmias are an important cause
of death in cardiac amyloidosis.
Morphology
On histologic examination, the amyloid deposition is always extracellular and begins
between cells, often closely adjacent to basement membranes. As the amyloid
accumulates, in the AL form, perivascular and vascular localizations are common.
Microscopically, routine stains reveal only amorphous, acellular, hyaline,
eosinophilic extracellular material. The most commonly used staining technique
uses the 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 so
called apple-green birefringence.
Prognosis The outlook for patients with generalized amyloidosis is poor, with the
mean survival time after diagnosis ranging from 1 to 3 years.
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