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AMYLOIDOSIS

 Extracellular deposition of fibrillar proteins
which are responsible for tissue damage and
functional compromise.

 These abnormal fibrils are produced by the
aggregation of misfolded proteins (which are
soluble in their normal folded configuration)
 The fibrillar deposits bind a wide variety of
proteoglycans and glycosaminoglycans, including
heparan sulfate and dermatan sulfate, and plasma
proteins, notably serum amyloid P component
(SAP).

 The presence of abundant charged sugar groups
in these adsorbed proteins give the deposits
staining characteristics that were thought to
resemble starch (amylose). Therefore, the
deposits were called amyloid,
PATHOGENESIS

 Amyloidosis is fundamentally a disorder of
protein misfolding.

 Amyloid is not a structurally homogeneous
protein, more than 20 (at last count, 23)
different proteins can aggregate and form
fibrils with the appearance of amyloid.
 Regardless of their derivation, all amyloid
deposits are composed of nonbranching fibrils,
7.5 to 10 nm in diameter, each formed of β-
sheet polypeptide chains that are wound
together .

 The dye Congo red binds to these fibrils and
produces a red-green dichroism
(birefringence), which is commonly used to
identify amyloid desposits in tissues
 Several factors may contribute to the aggregation of
certain proteins and the formation of fibrils that
deposit in extracellular tissues

 The protein may have a tendency to form aggregates
of misfolded forms but does so only when its
concentration reaches abnormally high levels.
 This may happen

as an individual ages (senile amyloidosis), or

when its production is increased (e.g., in chronic
inflammatory states), or

if excretion of the protein is impaired
(amyloidosis associated with long-term dialysis).
 A mutation may give rise to a form of a protein that
has a tendency to fold improperly and form
aggregates (hereditary amyloidosis).

 Limited proteolysis may generate a protein that
forms amyloid fibrils (amyloidosis associated with
Alzheimer disease).
 Of the more than 20 biochemically distinct forms of
amyloid proteins that have been identified, three are
most common:

1) The AL (amyloid light chain) protein is produced
by plasma cells and is made up of complete
immunoglobulin (Ig) light chains, the amino-
terminal fragments of light chains, or both.
 Only a few types of Ig light chains are prone to
forming aggregates, probably because they contain
amino acid residues that destabilize the domain
structure. As expected, 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
nonimmunoglobulin protein derived from a larger
(12-kD) serum precursor called SAA (serum
amyloid-associated) protein that is synthesized in
the liver..
 Increased production of SAA is probably not
sufficient to generate amyloid deposits. It is
believed that SAA is normally degraded to soluble
end products by macrophage-derived enzymes.
Defective proteolysis may produce misfolded,
incompletely degraded SAA, leading to aggregation
and deposition as AA fibrils.

 The production of this protein is increased in
inflammatory states as part of the "acute phase
response"; therefore this form of amyloidosis is
associated with chronic inflammatory disorders
3) Aβ amyloid is found in the cerebral lesions of
Alzheimer disease.

 Aβ is a 4-kD peptide that constitutes the core of
cerebral plaques and the amyloid deposits in
cerebral blood vessels in this disease.

 The Aβ protein is derived from a much larger
transmembrane glycoprotein called amyloid
precursor protein (APP)
 Several other proteins have been found in amyloid
deposits in a variety of clinical settings:

 Transthyretin (TTR) is a normal serum protein that
binds and transports thyroxine and retinol, hence
the name.

Mutations in the gene encoding transthyretin result
in the production of a protein (and its fragments)
that aggregate and form amyloid deposits. The
resultant diseases are called familial amyloid
polyneuropathies
 Transthyretin is also deposited in the heart of aged
individuals (senile systemic amyloidosis); in such
cases the protein is structurally normal, but it
accumulates at high concentrations.

 Some cases of familial amyloidosis are associated
with deposits of mutant lysozyme
 β2-microglobulin, a component of the MHC class I
molecules and a normal serum protein, has been
identified as the amyloid fibril subunit (Aβ2m) in
amyloidosis that complicates the course of patients
on long-term hemodialysis.
 This protein is present in high concentrations in the
serum of patients with renal disease and is retained in
the circulation because it is not efficiently filtered
through dialysis membranes.

 In some series, as many as 60% to 80% of patients on
long-term dialysis developed amyloid deposits in the
synovium, joints, and tendon sheaths

 Amyloid deposits derived from diverse precursors
such as hormones (procalcitonin) and keratin have
also been reported.
CLASSIFICATION
 May be systemic or localized,
 On clinical grounds, the systemic is subclassified
into primary amyloidosis when associated with
some immunocyte dyscrasia,

or secondary amyloidosis when it occurs as a
complication of an underlying chronic inflammatory
or tissue destructive process.

Hereditary or familial amyloidosis
PRIMARY AMYLOIDOSIS
 Usually systemic in distribution and is of the AL
type.

 The most common form of amyloidosis.

 Eg: amyloidosis associated with multiple myeloma

The malignant B cells characteristically synthesize
abnormal amounts of a single specific Ig
(monoclonal gammopathy), producing an M
(myeloma) protein spike on serum electrophoresis
 In addition to the synthesis of whole Ig molecules,
plasma cells may also synthesize and secrete either
the γ or κ light chain, also known as Bence Jones
proteins

 These are present in the serum of as many as 70% of
patients with multiple myeloma, and almost all
patients with myeloma who develop amyloidosis
have Bence Jones proteins in the serum or urine, or
both.
 Only 6% to 15% of myeloma patients who have free
light chains develop amyloidosis.

 The presence of Bence Jones proteins, though
necessary, is by itself not sufficient to produce
amyloidosis.

 Other variables, such as the type of light chain
produced and its catabolism, contribute to the
"amyloidogenic potential" and influence the
deposition of Bence Jones proteins.
 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.
 In virtually all such cases, patients have a modest
increase in the number of plasma cells in the bone
marrow, and monoclonal immunoglobulins or free
light chains can be found in the serum or urine.

 Clearly, these patients have an underlying B-cell
dyscrasia in which production of an abnormal
protein, rather than production of tumor masses, is
the predominant manifestation.
Reactive Systemic Amyloidosis

 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.
 The feature common to most cases of reactive
systemic amyloidosis is protracted cell injury
occurring in a spectrum of infectious and
noninfectious chronic inflammatory conditions.
Classically, tuberculosis, bronchiectasis, and chronic
osteomyelitis were the most common causes

 most frequently in the setting of chronic
inflammation caused by autoimmune states (e.g.,
RA, ankylosing spondylitis, and inflammatory
bowel disease
 RA is particularly prone to develop amyloidosis,
with amyloid deposition seen in as many as 3% of
such patients.

 Chronic skin infections caused by "skin-popping"
of narcotics are also associated with amyloid
deposition.

 May also occur in association with tumors not
derived from immune cells, the two most common
being renal cell carcinoma and Hodgkin
lymphoma.
Familial (Hereditary) Amyloidosis
 Most are rare and occur in limited geographic areas.

 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.

 This disorder is encountered largely in individuals
of Armenian, Sephardic Jewish, and Arabic origins
 Associated with widespread tissue involvement

 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.
 The gene for familial Mediterranean fever has been
cloned, and its product is called pyrin; although its
exact function is not known, it has been suggested that
pyrin is responsible for regulating acute inflammation,
presumably by inhibiting the function of neutrophils.

 With a mutation in this gene, minor traumas unleash a
vigorous, tissue-damaging inflammatory response.
 In contrast to familial Mediterranean fever, a group
of autosomal dominant familial disorders is
characterized by deposition of amyloid
predominantly in the peripheral and autonomic
nerves.

 These familial amyloidotic polyneuropathies have
been described in kindreds in different parts of the
world, for example, in Portugal, Japan, Sweden, and
the US.
Localized Amyloidosis
 The deposits may produce grossly detectable

nodular masses or be evident only on microscopic
examination.
 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. At least in some cases, the amyloid consists
of AL protein and may therefore represent a
localized form of immunocyte-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,
undifferentiated carcinomas of the stomach
in the islets of Langerhans in patients with type 2
diabetes mellitus.
 In these settings, the amyloidogenic proteins
seem to be derived either from polypeptide
hormones (medullary carcinoma) or from
unique proteins (e.g., islet amyloid
polypeptide).
Amyloid of Aging
 Senile systemic amyloidosis refers to the systemic

deposition of amyloid in elderly patients (usually in
their 70s and 80s).

 Because of the dominant involvement and related
dysfunction of the heart (typically presenting as a
restrictive cardiomyopathy and arrhythmias), this
form is also called senile cardiac amyloidosis.

 The amyloid in this form is composed of the normal
TTR molecule.
 In addition, another form predominantly affecting
only the heart results from the deposition of a
mutant form of TTR.

 Approximately 4% of the black population in the
United States is a carrier of the mutant allele, and
cardiomyopathy has been identified in both
homozygous and heterozygous patients
MORPHOLOGY:

 In amyloidosis secondary to chronic inflammatory
disorders, kidneys, liver, spleen, lymph nodes,
adrenals, and thyroid, as well as many other tissues,
are typically affected.

 Immunocyte-associated amyloidosis more often
involves the heart, gastrointestinal tract, respiratory
tract, peripheral nerves, skin, and tongue.
 The amyloidosis may or may not be apparent on
macroscopic examination.

 Often small amounts are not recognized until the
surface of the cut organ is painted with iodine and
sulfuric acid. This yields mahogany brown staining
of the amyloid deposits.

 When amyloid accumulates in larger amounts, the
organ is frequently enlarged and the tissue appears
gray with a waxy, firm consistency.
 Histologically, the amyloid deposition is
always extracellular and begins between cells,
often closely adjacent to basement membranes.

 As the amyloid accumulates, it encroaches on the
cells, in time surrounding and destroying them.

 In the immunocyte-associated form, perivascular
and vascular localizations are common
 The histologic diagnosis of amyloid is based almost
entirely on its staining characteristics.

 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

 . This reaction is shared by all forms of amyloid and
is caused by the crossed β-pleated configuration of
amyloid fibrils
 Confirmation can be obtained by electron
microscopy, which reveals amorphous nonoriented
thin fibrils.

 AA, AL, and ATTR types of amyloid can also be
distinguished by specific immunohistochemical
staining.
Kidney
 Amyloidosis of the kidney is the most common and

most serious involvement in the disease.

 Grossly, the kidney may appear unchanged, or it
may be abnormally large, pale, gray, and firm; in
long-standing cases, the kidney may be reduced in
size.

 Microscopically, the amyloid deposits are found
principally in the glomeruli, but they are also
present in the interstitial peritubular tissue as well as
in the walls of the blood vessels.
 The glomerulus first develops focal deposits within
the mesangial matrix and diffuse or nodular
thickenings of the basement membranes of the
capillary loops.

 With progression, the deposition encroaches on the
capillary lumina and eventually leads to total
obliteration of the vascular tuft
 The interstitial peritubular deposits are frequently
associated with the appearance of amorphous pink
casts within the tubular lumens, presumably of a
proteinaceous nature.

 Amyloid deposits may develop in the walls of
blood vessels of all sizes, often causing marked
vascular narrowing
Spleen
 Moderate or even marked enlargement(200-800gm).

 One of two patterns may develop. The deposits may
be virtually limited to the splenic follicles,
producing tapioca-like granules on gross
examination ("sago spleen"), or the involvement
may affect principally the splenic sinuses and
eventually extend to the splenic pulp, forming large,
sheetlike deposits ("lardaceous spleen"). In both
patterns the spleen is firm in consistency, and cut
surfaces reveal pale gray, waxy deposits
Liver
 Massive enlargement (as much as 9000 gm). In such

advanced cases the liver is extremely pale, grayish,
and waxy on both the external surface and the cut
section. Histologically, amyloid deposits first
appear in the space of Disse and then progressively
enlarge to encroach on the adjacent hepatic
parenchyma and sinusoids

 The trapped liver cells undergo compression atrophy
and are eventually replaced by sheets of amyloid;
function may be preserved even in the setting of
severe involvement
Heart

 Either as isolated organ involvement or as part of a
systemic distribution.

 When accompanied by systemic involvement, it is
usually associated with immunocyte dyscrasias.

 The isolated form (senile amyloidosis) is usually
confined to older individuals..
 The deposits may not be evident on gross
examination, or they may cause minimal to moderate
cardiac enlargement

 The most characteristic gross findings are gray-pink,
dewdrop-like subendocardial elevations, particularly
evident in the atrial chambers.

 On histologic examination, deposits are typically
found throughout the myocardium, beginning
between myocardial fibers and eventually causing
their pressure atrophy
Other Organs
 Encountered in systemic disease.

 The adrenals, thyroid, and pituitary are common
sites . In this case also the amyloid deposition
begins in relation to stromal and endothelial cells
and progressively encroaches on the parenchymal
cells.

 Surprisingly, large amounts of amyloid may be
present in any of these endocrine glands without
apparent disturbance of function.
 In the gastrointestinal tract, a relatively favored site,
amyloid may be found at all levels, sometimes
producing tumorous masses that must be
distinguished from neoplasms.

 Nodular depositions in the tongue may produce
macroglossia.
 On the basis of the frequent involvement of the
gastrointestinal tract in systemic cases, gingival,
intestinal, and rectal biopsies serve in the diagnosis of
suspected cases.

 Deposition of β2-microglobulin amyloid in patients
receiving long-term dialysis occurs most commonly
in the carpal ligaments of the wrist, resulting in
compression of the median nerve (carpal tunnel
syndrome
CLINICAL FEATURES
 Nonspecific complaints such as weakness, fatigue,
and weight loss are the most common initial
symptoms.
 Later by renal disease, hepatomegaly,
splenomegaly, or cardiac abnormalities.
 Renal involvement giving rise to severe proteinuria
is often 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
 The diagnosis of amyloidosis may be suspected
from the clinical signs and symptoms and from
some of the findings mentioned;

 Biopsy and subsequent Congo red staining is the
most important tool in the diagnosis of amyloidosis.

 In general, biopsy is taken from the organ suspected
to be involved. For example, renal biopsy is useful
in the presence of urinary abnormalities. Rectal and
gingival biopsy specimens contain amyloid in as
many as 75% of cases with generalized amyloidosis.
 Examination of abdominal fat aspirates stained with
Congo red is a simple, low-risk method.

 In suspected cases of AL amyloidosis, serum and
urinary protein electrophoresis and
immunoelectrophoresis should be performed.

 Bone marrow aspirate in such cases usually shows
plasmacytosis, even if skeletal lesions of multiple
myeloma are not present
 The outlook for patients with generalized
amyloidosis is poor, with the mean survival time
after diagnosis ranging from 1 to 3 years.

 In AA amyloidosis, the prognosis depends to some
extent on the control of the underlying condition.
 Patients with myeloma-associated amyloidosis have
a poorer prognosis, although they may respond to
cytotoxic drugs used to treat the underlying
disorder.

 Resorption of amyloid after treatment of the
associated condition has been reported, but this is a
rare occurrence.