AMYLOIDOSIS
Amyloidosis
is a multi-system disease in which amyloid protein fibrils deposit and
accumulate in various organs, where they cause progressive dysfunction. A wide
range of signs and symptoms may be seen depending on the specific organ systems
involved.
PATHOPHYSIOLOGY
Amyloid
fibrils are rigid, nonbranching, linear fibrils that are 8 to 10 nm wide. They
are composed of normally soluble proteins that become misfolded, resulting in
structural abnormalities that promote aggregation. Several factors can lead to
protein misfolding and fibril formation, such as aging (i.e., transthyretin in
senile amyloidosis); elevated serum concentrations (i.e., 2 microglobulin in
dialysis-related amyloidosis); and inherited mutations (i.e., hereditary
amyloidosis). Over 20 different proteins have been identified to have
amyloidogenic potential. The amyloid fibril structure is the same irrespective
of the precursor protein.
In addition
to the misfolded proteins, all amyloid fibrils contain a glycoprotein called
serum amyloid P component (SAP), which renders them resistant to proteolysis.
In addition, fibrils contain glycosaminoglycans, such as heparan sulfate, that
play an important role in fibril assembly and the binding of fibrils to target
tissues.
It is not
entirely clear how deposition of amyloid fibers leads to organ dysfunction. It
appears probable, however, that fibril accumulation disrupts normal tissue
architecture, and that protofibrils (intermediate fibril structures) cause
oxidative stress that triggers apoptosis.
The
particular organ distribution of amyloid fibrils appears to depend on poorly
understood features of the precursor protein. The amyloid fibrils most often
associated with renal disease are formed either by immunoglobulin light chains
(AL amyloidosis) or serum amyloid A (AA amyloidosis).
AL (primary)
amyloidosis occurs in the setting of an abnormal clonal proliferation of plasma
cells. During this proliferation, the light chains acquire proamyloidogenic
mutations. Such mutations do not always occur when light chains are
overproduced, as evidenced by the fact that only a minority of patients with
multiple myeloma develop AL amyloidosis. The annual incidence of AL amyloidosis
is 4.5 cases per 100,000 individuals, and it is the most common systemic
amyloidosis in North America. It typically affects patients over the age of 40.
AA (secondary)
amyloidosis occurs in the setting of chronic inflammatory diseases. The
precursor protein is serum amyloid A (SAA), an acute phase reactant that is
overproduced in chronic inflammatory states. Through a complex, incompletely
understood mechanism, SAA is cleaved and undergoes a conformational change that
leads to fibril formation. About half of AA amyloidosis cases are associated
with rheumatoid arthritis. Other causes of secondary amyloidosis include
ankylosing spondylitis, psoriatic arthritis, chronic pyogenic infections,
inflammatory bowel disease, cystic fibrosis, neoplasms, and familial
Mediterranean fever.
In both AA
and AL amyloidosis, the renal manifestations depend on the location of fibril
deposition. In the majority of renal amyloidosis cases, amyloid fibrils deposit
in the glomerulus, causing proteinuria that is typically in the nephrotic
range. Additional signs and symptoms are often consistent with the nephrotic syndrome (see
Plate 4-7), including edema, hypercholesterolemia, and hypoalbuminemia. Renal
function is usually preserved or only slightly impaired. Urine sediment may
reveal lipids or fatty casts but should not contain cells or cellular casts. In
a small number of cases, amyloid may deposit in the renal microvasculature,
causing a slowly progressive loss of renal function without proteinuria. In
even rarer cases, fibrils may deposit in the tubules, causing functional defects
such as distal renal tubular acidosis, nephrogenic diabetes insipidus, or the renal Fanconi syndrome.
Both AL and
AA amyloidosis may also cause disease in other organ systems. Myocardial
deposition is common, resulting in signs and symptoms of restrictive
cardiomyopathy. Hepatic deposition leads to hepatomegaly and abnormal liver
function tests. Peripheral nervous deposition can cause sensory, motor, and
autonomic abnormalities. Soft tissue deposition may manifest as macroglossia and carpal
tunnel syndrome.
Amyloidosis
should be on the differential diagnosis for any adult who presents with
idiopathic nephrotic syndrome, especially in the presence of unexplained heart
failure and peripheral and/or autonomic neuropathy. The presence of a chronic
inflammatory process, such as rheumatoid arthritis, suggests possible secondary
amyloidosis. A monoclonal paraprotein spike on immunofixation electrophoresis of
serum or urine suggests the diagnosis of AL amyloidosis.
A tissue
diagnosis is the gold standard for diagnosis, and a renal biopsy may be
performed in adults with renal manifestations.
Light
microscopy reveals nodular glomerulosclerosis, with deposits of amorphous
material seen in the mesangium and extending into the capillary loops. The
mesangial depositions can resemble Kimmelstiel-Wilson nodules seen in diabetic
nephropathy, but they stain periodic acid-Schiff (PAS) more weakly. A
characteristic feature of amyloid fibrils is their ability to stain with Congo
Red, which causes them to exhibit characteristic apple-green birefringence
under polarized light. AL and AA amyloidosis can be differentiated by
immunofluorescence (IF) staining, which is positive for lambda or kappa light
chains in AL amyloidosis, and for SAA in AA amyloidosis.
Electron
microscopy reveals the presence of randomly organized amyloid fibrils in the
mesangium and glomerular basement membrane. The fibrils are approximately 8 to
10 nm in diameter and can be differentiated from the fibrils of immunotactoid
and fibrillary glomerulonephritis by their distribution and size. The fibrils in
immunotactoid glomerulonephritis are composed of hollow tubules 30 to 50 nm in
size, arranged in parallel stacks, whereas the fibrils in fibrillary
glomerulonephritis range from 16 to 24 nm.
Somewhat
less invasive diagnostic tests than a renal biopsy include abdominal fat or
rectal biopsy. These are highly specific but only moderately sensitive (70% to
80%). Thus if amyloidosis is strongly suspected based on clinical history,
these superficial biopsies may be performed before renal biopsy. If these tests
are negative, however, renal biopsy should be performed.
If AL
amyloidosis is diagnosed on tissue biopsy, bone marrow biopsy is typically
performed to determine the plasma cell burden and rule out the presence of
multiple myeloma and other dyscrasias.
TREATMENT
In general,
there are two major approaches to the treatment of amyloidosis. The most common
approach is to reduce the production of precursor protein. AL production can be
targeted using chemotherapy (often using some combination of melphalan,
thalidomide, proteosome inhibitors, and steroids) or stem cell trans-
plantation. AA production can be reduced by treating the underlying inflammatory
disease. In rheumatoid arthritis, for example, anticytokine therapy may be
helpful. In chronic infections, eradication of the focus of infection with
appropriate measures, including anti-microbial agents, should be the focus.
The second
approach is to destabilize the amyloid fibril by targeting its SAP or
glycosaminoglycan component. An example of this approach is the compound
eprodisate, which attaches to the glycosaminoglycan binding sites of amyloid
fibrils in tissues, leading to fibril destabilization.
No matter
how the primary disease process is treated, patients should receive
conservative management for symptoms of nephrotic syndrome, including diuretics
and salt restriction.
PROGNOSIS
In AL
amyloidosis, the prognosis depends on the degree of systemic involvement
(especially cardiac involvement) and the degree to which therapy reduces free light chain
production. Although AL amyloidosis was previously considered a rapidly fatal
disease, patient survival appears to be increasing with current treatment
regimens.
In AA
amyloidosis, the prognosis depends on the activity of the underlying disease,
and infections are the major cause of death. There have been well-documented
cases of remission of AA amyloidosis with control of the infectious source.
