182 C H A P T E R 5
Diseases of the Immune System
in 1995–1996 to less than 4 per 100,000. Many AIDS-
associated disorders, such as opportunistic infections with
P. jiroveci and Kaposi sarcoma, now are uncommon. Effec-
tive anti-retroviral therapy also has reduced the transmis-
sion of the virus, especially from infected mothers to
newborns.
Despite these dramatic improvements, several new
complications associated with HIV infection and its
treatment have emerged. Some patients with advanced
disease who are given anti-retroviral therapy develop a
paradoxical clinical deterioration during the period of
recovery of the immune system despite increasing CD4+
T-cell counts and decreasing viral load. This disorder,
called the immune reconstitution inflammatory syndrome,
is not understood but is postulated to be a poorly regu-
lated host response to the high antigenic burden of per-
sistent microbes. Perhaps a more important complication
of long-term anti-retroviral therapy pertains to adverse
side effects of the drugs. These include lipoatrophy (loss
of facial fat), lipoaccumulation (excess fat deposition cen-
trally), elevated lipids, insulin resistance, peripheral neu-
ropathy, and premature cardiovascular, kidney, and liver
disease. Finally, non-AIDS morbidity is far more common
than classic AIDS-related morbidity in long-term HAART-
treated patients. Major causes of morbidity are cancer and
accelerated cardiovascular disease. The mechanism for
these non-AIDS–related complications is not known, but
persistent inflammation and T-cell dysfunction may have
a role.
MORPHOLOGY
Changes in the tissues (with the exception of the brain) are
neither specific nor diagnostic. Common pathologic features of
AIDS include opportunistic infections, Kaposi sarcoma, and B-cell
lymphomas. Most of these lesions are discussed elsewhere,
because they also occur in individuals who do not have HIV
infection. Lesions in the central nervous system are described in
Chapter 23.
Biopsy specimens from enlarged lymph nodes in the early
stages of HIV infection reveal a marked hyperplasia of B-cell fol-
licles, which often take on unusual, serpiginous shapes. The
mantle zones that surround the follicles are attenuated, and the
germinal centers impinge on interfollicular T cell areas. This
hyperplasia of B cells is the morphologic reflection of the poly-
clonal B cell activation and hypergammaglobulinemia seen in
HIV-infected individuals.
With disease progression, the frenzy of B cell proliferation
subsides and gives way to a pattern of severe lymphoid involution.
The lymph nodes are depleted of lymphocytes, and the organized
network of follicular dendritic cells is disrupted. The germinal
centers may even become hyalinized. During this advanced stage,
viral burden in the nodes is reduced, in part because of the
disruption of the follicular dendritic cells. These “burnt-out”
lymph nodes are atrophic and small and may harbor numerous
opportunistic pathogens, often within macrophages. Because of
profound immunosuppression, the inflammatory response to
infections both in the lymph nodes and at extranodal sites may
be sparse or atypical. For example, mycobacteria often fail to
evoke granuloma formation because CD4+ cells are deficient,
and the presence of these and other infectious agents may not
be apparent without special stains. As might be expected, lym-
phoid involution is not confined to the nodes; in later stages of
AIDS, the spleen and thymus also are converted to “wastelands”
that are virtually devoid of lymphocytes.
Despite impressive advances in our understanding and
treatment of HIV infection, the long-term prognosis of
patients with AIDS remains a concern. Although with
effective drug therapy the mortality rate has declined in
the United States, the treated patients still carry viral
DNA in their lymphoid tissues. Truly curative therapy
remains elusive. Similarly, although considerable effort
has been mounted to develop a protective vaccine, many
hurdles remain before this becomes a reality. Molecular
analyses have revealed an alarming degree of variation in
viral isolates from patients; this renders the task of pro-
ducing a vaccine extremely difficult. Recent efforts have
focused on producing broadly neutralizing antibodies
against relatively invariant portions of HIV proteins. At
present, therefore, prevention, public health measures,
and anti-retroviral drugs remain the mainstays in the
fight against AIDS.
SUMMARY
CLINICAL COURSE AND COMPLICATIONS OF
HIV INFECTION
• Progression of disease. HIV infection progresses through phases.
• Acute HIV infection. Manifestations of acute viral illness
• Chronic (latent) phase. Dissemination of virus, host immune
response, progressive destruction of immune cells.
• AIDS. Severe immune deficiency.
• Clinical features. Full-blown AIDS manifests with several com-
plications, mostly resulting from immune deficiency.
• Opportunistic infections
• Tumors, especially tumors caused by oncogenic viruses
• Neurologic complications of unknown pathogenesis
• Antiretroviral therapy has greatly decreased the incidence of
opportunistic infections and tumors but also has numerous
complications.
AMYLOIDOSIS
Amyloidosis is a condition associated with a number of
disorders in which extracellular deposits of fibrillar pro-
teins are responsible for tissue damage and functional
compromise. These abnormal fibrils are produced by the
aggregation of improperly folded proteins (which are
soluble in their normal folded configuration). The fibrillar
deposits bind a wide variety of proteoglycans and glycos-
aminoglycans, which contain charged sugar groups that
give the deposits staining characteristics thought to resem-
ble those of starch (amylose). Therefore, the deposits were
called amyloid, a name that is firmly entrenched despite the
realization that the deposits are unrelated to starch.

Pathogenesis of Amyloid Deposition
Amyloid deposits can occur in a variety of conditions, in
each of which the protein composition is different.
Although amyloid always has the same morphologic
appearance, it is biochemically heterogeneous. In fact, at
least 30 different proteins can aggregate to form fibrils with
the appearance of amyloid. Regardless of their derivation,
all amyloid deposits are composed of nonbranching fibrils,
each formed of intertwined polypeptides in a β pleated
sheet conformation (Fig. 5.41). Approximately 95% of the
amyloid material consists of fibril proteins, the remaining
5% being various glycoproteins.
The three most common forms of amyloid are the
following:
• AL (amyloid light chain) amyloid is made up of complete
immunoglobulin light chains, the amino-terminal frag-
ments of light chains, or both.
• AA (amyloid-associated) amyloid is composed of an 8500-
dalton protein derived by proteolysis from a larger
precursor in the blood called SAA (serum amyloid-
associated) protein, which is synthesized in the liver.
• β-amyloid protein (Aβ) is a 4000-dalton peptide that is
derived by proteolysis from a much larger transmem-
brane glycoprotein, called amyloid precursor protein.
Congo
red B mately 2000 to 3000 new cases each year in the United
A C
Fig. 5.41  Structure of amyloid. (A) A schematic diagram of an amyloid fiber
showing four fibrils (there can be as many as six in each fiber) wound around
one another with regularly spaced binding of the Congo red dye. (B) Congo
red staining shows apple-green birefringence under polarized light, a diag-
nostic feature of amyloid. (C) Electron micrograph of 7.5- to 10-nm amyloid
fibrils. (From Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J
Med 349:583–596, 2003.)
Amyloidosis 183
Many other proteins also can deposit as amyloid in a
variety of clinical settings. Some of the most clinically
important examples are mentioned in the following section.
Classification of Amyloidosis and Mechanisms of
Amyloid Formation
Amyloidosis results from abnormal folding of proteins,
which assume a β pleated sheet conformation, aggregate,
and deposit as fibrils in extracellular tissues. Normally,
intracellular misfolded proteins are degraded in protea-
somes and extracellular protein aggregates are taken up
and degraded by macrophages. In amyloidosis, these
quality control mechanisms fail and fibrillar proteins accu-
mulate outside of cells. The proteins that form amyloid
fall into two general categories (Fig. 5.42): (1) normal
proteins that have an inherent tendency to associate and
form fibrils, particularly when produced in increased
amounts; and (2) mutant proteins that are prone to mis-
folding and aggregation. The mechanisms of deposition of
different types of amyloid are discussed next along with
classification.
Because a given form of amyloid (e.g., AA) may be
associated with diverse clinical settings, we will follow a
classification that takes into account clinical and biochemi-
cal features (Table 5.16). Amyloid may be systemic (gener-
alized), involving several organ systems, or it may be
localized to a single organ, such as the heart. On clinical
grounds, the systemic pattern is subclassified into primary
amyloidosis when it is associated with a clonal plasma cell
proliferation, or secondary amyloidosis when it occurs as
a complication of an underlying chronic inflammatory or
tissue-destructive process. Hereditary or familial amyloi-
dosis constitutes a separate, heterogeneous group with
several distinctive patterns of organ involvement.
Primary Amyloidosis: Plasma Cell Proliferations Asso-
ciated With Amyloidosis.  Amyloid in this category is of
the AL type and is usually systemic in distribution. This is
the most common form of amyloidosis, with approxi-
States. It is caused by a clonal proliferation of plasma cells
that synthesize abnormal Ig molecules. The AL type of
systemic amyloidosis occurs in 5% to 15% of individuals
with multiple myeloma, a plasma-cell tumor characterized
by excessive production of free immunoglobulin light
chains (Chapter 12). The free, unpaired κ or λ light chains
(referred to as Bence Jones protein) are prone to aggregating
and depositing in tissues as amyloid. Since the majority of
myeloma patients do not develop amyloidosis, however, it
is clear that not all free light chains are equally likely to
produce amyloid. For unknown reasons, λ light chains are
approximately six times more likely to deposit as amyloid
than κ light chains.
Most persons with AL amyloid do not have multiple
myeloma or any other overt B cell neoplasm; such cases
have been traditionally classified as primary amyloidosis,
because their clinical features derive solely from the effects
of amyloid deposition rather than formation of tumor
masses. In virtually all such cases, however, monoclonal
immunoglobulins or free light chains, or both, can be found
in the blood or urine. Most of these patients also have a
184 C H A P T E R 5 Diseases of the Immune System

PRODUCTION OF ABNORMAL PRODUCTION OF NORMAL

AMOUNTS OF PROTEIN AMOUNTS OF MUTANT
PROTEIN (e.g., transthyretin)

Native folded Acquired

Chronic inflammation Inherited mutations
protein mutations

Macrophage
Monoclonal activation
B-lymphocyte
proliferation
Amyloidogenic intermediate
Interleukins 1 and 6
(e.g., misfolded protein)

Plasma
Liver
cells
cells

Monomers assemble to Immunoglobulin Mutant

SAA Protein
form β-sheet structure light chains transthyretin

Limited Limited Aggregation

proteolysis proteolysis

FIBRIL AL PROTEIN AA PROTEIN ATTR PROTEIN

A B C
Fig. 5.42  Pathogenesis of amyloidosis. (A) General mechanism of formation of amyloid fibrils. (B) Formation of amyloid from excessive production of proteins
prone to misfolding. (C) Formation of amyloid from mutant protein.

modest increase in the number of plasma cells in the bone
marrow, which presumably secrete the precursors of AL
protein.
Reactive Systemic Amyloidosis.  The amyloid deposits
in this pattern are systemic in distribution and are com-
posed of AA protein. This category was previously referred
to as secondary amyloidosis because it is secondary to an
associated inflammatory condition. At one time, tubercu-
losis, bronchiectasis, and chronic osteomyelitis were the
most important underlying conditions, but currently, these
conditions frequently resolve with antibiotic treatment and
less often lead to amyloidosis. More commonly now, reac-
tive systemic amyloidosis complicates rheumatoid arthri-
tis, other connective tissue disorders such as ankylosing
spondylitis, and inflammatory bowel disease, particularly

Table 5.16  Classification of Amyloidosis

Major Fibril Chemically Related
Clinicopathologic Category Associated Diseases Protein Precursor Protein
Systemic (Generalized) Amyloidosis
Plasma cell proliferations with Multiple myeloma and other monoclonal AL Immunoglobulin light chains,
amyloidosis (primary amyloidosis) plasma cell proliferations chiefly λ type
Reactive systemic amyloidosis Chronic inflammatory conditions AA SAA
(secondary amyloidosis)
Hemodialysis-associated amyloidosis Chronic renal failure Aβ2m β2-microglobulin
Hereditary Amyloidosis
Familial Mediterranean fever AA SAA
Familial amyloidotic neuropathies ATTR Transthyretin
(several types)
Systemic senile amyloidosis ATTR Transthyretin
Localized Amyloidosis
Senile cerebral Alzheimer disease Aβ APP
Endocrine Type 2 diabetes
Medullary carcinoma of thyroid A Cal Calcitonin
Islets of Langerhans AIAPP Islet amyloid peptide
Isolated atrial amyloidosis AANF Atrial natriuretic factor

Crohn disease and ulcerative colitis. Among these, the
most frequent associated condition is rheumatoid arthritis.
Amyloidosis is reported to occur in approximately 3% of
patients with rheumatoid arthritis and is clinically signifi-
cant in one half of those affected. Heroin abusers who inject
the drug subcutaneously also have a high occurrence rate
of generalized AA amyloidosis. The chronic skin infec-
tions, which cause the “skin-popping” associated with
injection of narcotics, seem to be responsible for the amy-
loidosis. Reactive systemic amyloidosis also may occur in
association with certain cancers, the most common being
renal cell carcinoma and Hodgkin lymphoma.
In AA amyloidosis, SAA synthesis by liver cells is stim-
ulated by cytokines such as IL-6 and IL-1 that are produced
during inflammation; thus, long-standing inflammation
leads to a sustained elevation of SAA levels. While SAA
levels are increased in all cases of inflammation, only a
small subset get amyloidosis. It seems that in some patients
SAA breakdown produces intermediates that are prone to
forming fibrils.
Heredofamilial Amyloidosis.  A variety of familial forms
of amyloidosis have been described. Most are rare and
occur in limited geographic areas. The most common and
best studied is an autosomal recessive condition called
familial Mediterranean fever, which is encountered largely in
individuals of Armenian, Sephardic Jewish, and Arabic
origins. This is an “autoinflammatory” syndrome associ-
ated with excessive production of the cytokine IL-1 in
response to inflammatory stimuli. It is characterized by
attacks of fever accompanied by inflammation of serosal
surfaces that manifests as peritonitis, pleuritis, and syno-
vitis. The gene for familial Mediterranean fever encodes a
protein called pyrin that is important in dampening the
response of innate immune cells, particularly neutrophils,
to inflammatory mediators. The amyloid seen in this dis-
order is of the AA type, suggesting that it is related to the
recurrent bouts of inflammation.
In contrast to familial Mediterranean fever, a group
of autosomal dominant familial disorders is character-
ized by deposition of amyloid made up of fibrils derived
from mutant transthyretin (TTR). TTR is a transporter
of the hormone thyroxine. Remarkably, specific TTR
mutant polypeptides tend to form amyloid in different
organs; thus, in some families, deposits are seen mainly
in peripheral nerves (familial amyloidotic polyneuropa-
thies), whereas in others cardiac deposits predominate.
The mutated form of the TTR gene that leads to cardiac
amyloidosis is carried by approximately 4% of the black
population in the United States, and cardiomyopathy has
been identified in both homozygous and heterozygous
patients. The precise prevalence of patients with this muta-
tion who develop clinically manifest cardiac disease is
not known.
Hemodialysis-Associated Amyloidosis.  Patients on
long-term hemodialysis for renal failure can develop
amyloid deposits derived from β2-microglobulin. This
protein is present in high concentrations in the serum of
individuals with renal disease, and in the past it was
retained in the circulation because it could not be filtered
through dialysis membranes. With new dialysis filters, the
Amyloidosis 185
incidence of this complication has decreased substantially.
The classical features of this form of amyloidosis are the
triad of scapulohumeral periarthritis, carpal tunnel syn-
drome, and flexor tenosynovitis of the hand.
Localized Amyloidosis.  Sometimes, amyloid deposits
are 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. Nodular 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 associ-
ated with these amyloid masses. At least in some cases, the
amyloid consists of AL protein and may therefore repre-
sent a localized form of plasma cell–derived amyloid.
Endocrine Amyloid.  Microscopic deposits 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, and in the islets of Langerhans
in individuals with type 2 diabetes mellitus. In these set-
tings, the amyloidogenic proteins seem to be derived either
from polypeptide hormones (e.g., medullary carcinoma) or
from unique proteins (e.g., islet amyloid polypeptide).
Amyloid of Aging.  Several well-documented forms of
amyloid deposition occur with aging. Senile systemic amy-
loidosis refers to the systemic deposition of amyloid in
elderly patients (usually in their seventies and eighties).
Because of the dominant involvement and related dysfunc-
tion of the heart, this form was previously called senile
cardiac amyloidosis. Those who are symptomatic present
with a restrictive cardiomyopathy and arrhythmias
(Chapter 11). The amyloid in this form, in contrast to famil-
ial forms, is derived from normal TTR.
MORPHOLOGY
There are no consistent or distinctive patterns of organ or tissue
distribution of amyloid deposits in any of the categories cited,
but a few generalizations can be made. In AA amyloidosis second-
ary to chronic inflammatory disorders, kidneys, liver, spleen,
lymph nodes, adrenal glands, thyroid glands, and many other
tissues are typically affected. Although AL amyloidosis associated
with plasma cell proliferations cannot reliably be distinguished
from the AA form by its organ distribution, it more often involves
the heart, gastrointestinal tract, respiratory tract, peripheral
nerves, skin, and tongue. The localization of amyloid deposits in
the hereditary syndromes is varied. In familial Mediterranean
fever, the amyloidosis is of the AA type and accordingly may be
widespread, involving the kidneys, blood vessels, spleen, respira-
tory tract, and (rarely) liver.
Amyloid may be appreciated macroscopically when it accu-
mulates in large amounts. The organ is frequently enlarged, and
the tissue appears gray and has a waxy, firm consistency. Histo-
logically, the amyloid deposition is always extracellular and begins
between cells, often closely adjacent to basement membranes
186 C H A P T E R 5 Diseases of the Immune System
(Fig. 5.43A). As the amyloid accumulates, it encroaches on the
cells, in time surrounding and destroying them. In the form asso-
ciated with plasma cell proliferation, perivascular and vascular
deposits are common.
The diagnosis of amyloidosis is based on histopathol-
ogy. With the light microscope and hematoxylin and eosin stains,
amyloid appears as an amorphous, eosinophilic, hyaline, extracel-
lular substance.To differentiate amyloid from other hyaline mate-
rials (e.g., collagen, fibrin), a variety of histochemical stains are
used. The most widely used is the Congo red stain, which under
ordinary light gives a pink or red color to tissue deposits, but
far more striking and specific is the green birefringence of the
stained amyloid when observed by polarizing microscopy (Fig.
5.43B). This staining reaction is shared by all forms of amyloid
and is imparted by the crossed β-pleated sheet configuration of
amyloid fibrils. Confirmation can be obtained by electron
microscopy, which reveals amorphous nonoriented thin fibrils.
Subtyping of amyloid is most reliably done by mass spectroscopy,
as immunohistochemical stains are not entirely sensitive or
specific.
The pattern of organ involvement in different forms of amy-
loidosis is variable.
Kidney. Amyloidosis of the kidney is the most common and
potentially the most serious form of organ involvement. Grossly,
the kidneys may be of normal size and color, or in advanced
cases they may be shrunken because of ischemia caused by
vascular narrowing induced by the deposition of amyloid within
arterial and arteriolar walls. Histologically, the amyloid is depos-
ited primarily in the glomeruli, but the interstitial peritubular
tissue, arteries, and arterioles are also affected. The glomerular
deposits first appear as subtle thickenings of the mesangial
matrix, accompanied usually by uneven widening of the base-
ment membranes of the glomerular capillaries. In time, deposits
in the mesangium and along the basement membranes cause
capillary narrowing and distortion of the glomerular vascular
tuft. With progression of the glomerular amyloidosis, the capil-
lary lumens are obliterated and the obsolescent glomerulus is
replaced by confluent masses or interlacing broad ribbons of
amyloid.
A B
Fig. 5.43  Amyloidosis. (A) A section of liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids.
(B) Note the yellow-green birefringence of the deposits when observed by a polarizing microscope. (B, Courtesy of Dr. Trace Worrell and Sandy Hinton, Depart-
ment of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)
Spleen. Amyloidosis of the spleen may be inapparent grossly
or may cause moderate to marked splenomegaly (up to 800 g).
For mysterious reasons, two distinct patterns of deposition are
seen. In one, the deposits are largely limited to the splenic fol-
licles, producing tapioca-like granules on gross inspection, desig-
nated sago spleen. In the other pattern, the amyloid involves the
walls of the splenic sinuses and connective tissue framework in
the red pulp. Fusion of the early deposits gives rise to large,
maplike areas of amyloidosis, creating what has been designated
lardaceous spleen.
Liver. The deposits may be inapparent grossly or may cause
moderate to marked hepatomegaly. Amyloid appears first in the
space of Disse and then progressively encroaches on adjacent
hepatic parenchymal cells and sinusoids. In time, deformity, pres-
sure atrophy, and disappearance of hepatocytes occur, causing
total replacement of large areas of liver parenchyma. Vascular
involvement and deposits in Kupffer cells are frequent. Liver
function is usually preserved despite sometimes quite extensive
involvement.
Heart. Amyloidosis of the heart (Chapter 11) may occur in
any form of systemic amyloidosis. It also is the major organ
involved in senile systemic amyloidosis.The heart may be enlarged
and firm, but more often it shows no appreciable change on gross
inspection. Histologically the deposits begin as focal subendocar-
dial accumulations and within the myocardium between the
muscle fibers. Expansion of these myocardial deposits eventually
causes pressure atrophy of myocardial fibers. When the amyloid
deposits are subendocardial, the conduction system may be
damaged, accounting for the electrocardiographic abnormalities
noted in some patients.
Other Organs. Nodular depositions in the tongue may
cause macroglossia, giving rise to the designation tumor-forming
amyloid of the tongue. The respiratory tract may be involved
focally or diffusely from the larynx down to the smallest bron-
chioles. A distinct form of amyloid is found in the brains of
patients with Alzheimer disease. It may be present in so-called
“plaques” as well as blood vessels (Chapter 23). Amyloidosis of
peripheral and autonomic nerves is a feature of several familial
amyloidotic neuropathies.

Clinical Features
Amyloidosis may be found as an unsuspected anatomic
change, having produced no clinical manifestations, or it
may cause serious clinical problems and even death. The
symptoms depend on the magnitude of the deposits and
on the sites or organs affected. Clinical manifestations at
first are often entirely nonspecific, such as weakness,
weight loss, lightheadedness, or syncope. Somewhat more
specific findings appear later and most often relate to renal,
cardiac, and gastrointestinal involvement.
Renal involvement gives rise to proteinuria that may be
severe enough to cause the nephrotic syndrome (Chapter
14). Progressive obliteration of glomeruli in advanced
cases ultimately leads to renal failure and uremia. Renal
failure is a common cause of death. Cardiac amyloidosis
may present insidiously as congestive heart failure. The
most serious aspects of cardiac amyloidosis are conduction
disturbances and arrhythmias, which may prove fatal.
Occasionally, cardiac amyloidosis produces a restrictive
pattern of cardiomyopathy and masquerades as chronic
constrictive pericarditis (Chapter 11). Gastrointestinal
amyloidosis may be asymptomatic, or it may present in a
variety of ways. Amyloidosis of the tongue may cause suf-
ficient enlargement and inelasticity to hamper speech and
swallowing. Depositions in the stomach and intestine may
lead to malabsorption, diarrhea, and disturbances in diges-
tion. Vascular amyloidosis causes vascular fragility that
may lead to bleeding, sometimes massive, that can occur
spontaneously or following seemingly trivial trauma.
Additionally, in some cases AL amyloid binds and inacti-
vates factor X, a critical coagulation factor, leading to a
life-threatening bleeding disorder.
The diagnosis of amyloidosis depends on the histologic
demonstration of amyloid deposits in tissues. The most
common sites biopsied are the kidney, when renal mani-
festations are present, or rectal or gingival tissues in
patients suspected of having systemic amyloidosis. Exami-
nation of abdominal fat aspirates stained with Congo red
can also be used for the diagnosis of systemic amyloidosis.
The test is quite specific, but its sensitivity is low. In sus-
pected cases of AL amyloidosis, serum and urine protein
electrophoresis and immunoelectrophoresis should be per-
formed. Bone marrow aspirates in such cases often show a
monoclonal population of plasma cells, even in the absence
of overt multiple myeloma. Scintigraphy with radiolabeled
serum amyloid P (SAP) component is a rapid and specific
test, since SAP binds to the amyloid deposits and reveals
their presence. It also gives a measure of the extent of
amyloidosis and can be used to follow patients undergoing
treatment. Mass spectroscopy is a useful tool for identifica-
tion of the protein component of amyloid. It can be per-
formed on paraffin embedded tissues.
The prognosis for individuals with generalized amyloi-
dosis is poor. Those with AL amyloidosis (not including
multiple myeloma) have a median survival of 2 years after
diagnosis. Individuals with myeloma-associated amyloi-
dosis have an even poorer prognosis. The outlook for indi-
viduals with reactive systemic amyloidosis is somewhat
better and depends to some extent on the control of the
underlying condition. Resorption of amyloid after treat-
ment of the associated condition has been reported, but this
is a rare occurrence. New therapeutic strategies aimed at
Amyloidosis 187
correcting protein misfolding and inhibiting fibrillogenesis
are being developed.
SUMMARY
AMYLOIDOSIS
• Amyloidosis is a disorder characterized by the extracellular
deposits of proteins that are prone to aggregate and form
insoluble fibrils.
• The deposition of these proteins may result from: excessive
production of proteins that are prone to aggregation; muta-
tions that produce proteins that cannot fold properly and tend
to aggregate; defective or incomplete proteolytic degradation
of extracellular proteins.
• Amyloidosis may be localized or systemic. It is seen in associa-
tion with a variety of primary disorders, including monoclonal
B-cell proliferations (in which the amyloid deposits consist of
immunoglobulin light chains); chronic inflammatory diseases
such as rheumatoid arthritis (deposits of amyloid A protein,
derived from an acute-phase protein produced in inflamma-
tion); Alzheimer disease (amyloid β protein); familial conditions
in which the amyloid deposits consist of mutated proteins (e.g.,
transthyretin in familial amyloid polyneuropathies); and hemo-
dialysis (deposits of β2-microglobulin, whose clearance is
defective).
• Amyloid deposits cause tissue injury and impair normal func-
tion by causing pressure on cells and tissues.They do not evoke
an inflammatory response.
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