1. Amyloidosis
Amyloidosis comprises a group of diseases characterized by
extracellular deposition of insoluble, fibrous amyloid proteins
in various body tissues.
ETIOLOGY.
Amyloid material is composed of microscopic fibrils that are
biochemically heterogeneous, with at least 20 different types
of protein fibril compositions. All amyloid deposits contain the
same nonfibrillar component, serum amyloid P. Amyloid fibril
deposition may have no apparent consequences, or it may
ultimately interfere with organ function.
The traditional amyloidosis classification system uses the
descriptive terms systemic and localized, which do not
designate the etiology or associated clinical manifestations.
The systemic, or multisystem, amyloidoses correspond to
clinical patterns of primary, secondary, familial, and dialysis-
related amyloidosis. The localized, or organ-limited,
amyloidoses are associated with aging and diabetes and
occur in isolated organs such as endocrine glands without
systemic involvement. The newer nomenclature of
amyloidoses is based on biochemical analysis and uses A
for amyloid followed by the abbreviation for the type of fibril
protein. The most common type of amyloidosis in the United
States, which was known as primary idiopathic amyloidosis
or myeloma-associated amyloidosis, has deposition of
amyloid composed of pieces of monoclonal immunoglobulin
light-chain (abbreviated to L) and is now referred to as AL
amyloidosis. Amyloidosis in persons with familial
Mediterranean fever (FMF), chronic infection, and chronic
inflammatory diseases involve amyloid A protein and was
formerly known as secondary or reactive amyloidosis, and is
2. now referred to as AA amyloidosis. AA amyloidosis is the
most common serious complication of FMF (see Chapter
162 ). Amyloid conditions associated with aging (Alzheimer
disease) as well as several rare autosomal dominant forms
of amyloidoses have fibril protein composed of variants of
the transport protein transthyretin (TTR) and are now
referred to as TTR amyloidosis.
EPIDEMIOLOGY.
AL amyloidosis is extremely rare in children and usually
occurs in persons of middle age or older. It represents a
plasma cell dyscrasia and can occur in isolation or along
with multiple myeloma.
Only AA amyloidosis affects children in appreciable
numbers, occurring in some persons with FMF, chronic
inflammatory diseases including juvenile rheumatoid arthritis
(JRA), ankylosing spondylitis, inflammatory bowel disease,
chronic infections such as tuberculosis, cystic fibrosis, and,
less commonly, systemic lupus erythematosus and juvenile
dermatomyositis. The factors that determine the risk for
amyloidosis as a complication of inflammation are not clear,
as many individuals with long-standing inflammatory disease
do not develop tissue amyloid deposition. AA amyloidosis
affects as many as 10% of children with JRA in some
European countries but is rarely seen as a complication of
seemingly similar disease in children in the United States
and Canada. Additionally, Armenians with FMF living in
Armenia are reported to have a significantly higher incidence
of amyloidosis than do their Armenian counterparts in North
America. There is also ethnic variability in the frequency of
amyloidosis, which among patients with FMF occurs in up to
60% of Turks, 27% of Sephardic Jews, and 1–2% of
Armenians living in the United States. Reasons for these
3. differences are unknown, although environmental and
genetic factors in addition to the underlying inflammatory
disease appear to have a role.
PATHOGENESIS.
The AA protein isolated from AA amyloidosis is the 76-amino
acid N-terminus fragment of serum amyloid A (SAA). SAA, a
polymorphic protein synthesized in the liver, is an acute-
phase reactant. Chronic inflammation results in elevated
levels of SAA, which is the precursor to the fibril formation of
AA amyloidosis. Three protein isoforms of SAA exist. SAA1
is the precursor of AA amyloidosis in majority of cases and
has 5 variants that differ from each other by amino acid
substitutions.
The factors responsible for determining the site of amyloid
deposition in any form of amyloidosis are unknown. AA
amyloidosis fibrils have been generated in tissue cultures by
incubating SAA with macrophages, which may explain
amyloid depositions in tissues such as the liver and spleen.
The increased deposition in the kidneys is related to a
different mechanism, possibly the glyco-oxidative
modification of the AA protein itself.
Amyloid deposits are composed of seemingly homogeneous
eosinophilic material that stains with Congo red dye and in
polarized light demonstrates the pathognomonic apple-green
birefringence. Amyloid can be recognized also by routine
hematoxylin and eosin(H&E)–staining.
CLINICAL MANIFESTATIONS.
Various patterns of organ dysfunction result from deposition
of different types of amyloid fibril protein material.
Regardless of the cause of amyloidosis, clinical symptoms
4. usually begin >10 yr after the onset of inflammatory disease.
The diagnosis is not usually established until the disease is
far advanced. The most common clinical presentation of AA
amyloidosis is renal dysfunction, ranging from proteinuria to
nephrotic syndrome and eventual renal failure. Involvement
of the gastrointestinal system is also frequent and usually
manifests as chronic diarrhea, gastrointestinal bleeding,
abdominal pain, and malabsorption. Anemia, hepatomegaly,
and splenomegaly may be present.
DIAGNOSIS.
The diagnosis of amyloidosis is established by biopsy
demonstrating amyloid fibril proteins in affected tissues. In
the presence of amyloidosis, renal biopsies are
contraindicated because of potential bleeding. The liver and
spleen are often affected but are not suitable sites for
biopsy. Biopsy sites that are more accessible include the
rectal mucosa, gingival tissue, and abdominal fat aspirate. A
method of microradiographic scintigraphy using serum
amyloid P component has been described as a useful tool
for the diagnosis as well as for the monitoring of the status of
amyloidosis.
LABORATORY FINDINGS.
Patients with JRA and AA amyloidosis usually show elevated
acute-phase reactants and high levels of immunoglobulins.
Specific laboratory testing is only possible for AL
amyloidosis. Most of these patients show increased plasma
cells in the bone marrow, and serum or urine monoclonal Ig
or free light chain. A biopsy showing amyloid deposition
along with a monoclonal serum protein distinguishes AL
amyloidosis from monoclonal gammopathy of uncertain
significance (MGUS), which is common in older adults.
5. TREATMENT.
The primary means of treatment of AA amyloidosis is
aggressive management of the underlying inflammatory or
infectious disease, which decreases levels of SAA protein.
Colchicine is effective in controlling the attacks of FMF and
also in preventing the development of amyloidosis
associated with FMF. Children with FMF who are
homozygous for M694V are at greater risk of developing
amyloidosis and should receive colchicine for life.
Unlike AA amyloidosis associated with FMF, AA amyloidosis
associated with JRA does not respond to colchicine therapy
but instead does respond to chlorambucil, which reverses
renal findings and prolongs the life of treated patients.
Chlorambucil is associated with chromosome breakage and
an unknown risk of subsequent malignancy. There is little
experience with other cytotoxic agents or with the therapy for
AA amyloidosis associated with other conditions. Anti–tumor
necrosis factor-α (TNF-α) therapy, with etanercept or
infliximab, is well tolerated and effective in reducing
proteinuria in patients with AA amyloidosis secondary to
inflammatory arthritides. Drugs that specifically prevent fibril
development are in development.
COMPLICATIONS AND PROGNOSIS.
End-stage renal failure is the underlying cause of death in
40–60% of cases of amyloidosis, with a median survival time
from diagnosis of 2–10 yr.
PREVENTION.
The primary means of preventing AA amyloidosis is
treatment of the underlying inflammatory or infectious
