Amyloidosis

Dilip K. Das, MBBS, MD, PhD, DSc, FRCPath.

Department of Pathology, Faculty of Medicine,
Kuwait University
 Amyloidosis: Definition
• Amyloidosis is a group of diseases in
which one or more organ systems in the
body accumulate deposits of abnormal
proteins known as amyloid.
• Amyloid: (1) is a pathologic proteinaceous
substance, (2) deposited between the cells in
various tissues and organs of the body, in a
wide variety of clinical settings and (3) with
progressive accumulation, encroaches on
and produces pressure atrophy of adjacent
cells.
Amyloid: Staining Characteristics

With light microscope and Congo red: Orange red

standard tissue stains (H&E), color under ordinary light
amyloid appears as an but when viewed in a
amorphous, eosinophilic, polarizing microscope, a
hyaline, extracellular characteristic green
substance. birefringence is imparted.
 Classification of Amyloidosis

I. Immunocyte-derived systemic amyloidosis (AL

amyloidosis). Primary amyloidosis.
II. Reactive systemic amyloidosis (AA amyloidosis).
Secondary amyloidosis.
III. Hemodialysis –Associated Amyloidosis
IV. Heredofamilial amyloidosis.
V. Localized amyloidosis: (A). Endocrine
associated, (B). Senile, and (C). Others.
 Immunocyte-derived Systemic
Amyloidosis
• Found in with 5 to 15% multiple myeloma patients and in patients with
B-cell dyscrasias (monoclonal B-cell proliferations).
• Amyloid is systemic indistribution (AL type) and derived from Ig light
chains (chiefly λ type).
• An excess of corresponding light chain is usually present in the blood
and secreted in urine as Bence-Jones protein
Organ involvement and its effect:
• Kidney involvement is a major feature and usual cause of death.
• Myocardium : refractory heart failure.
• Tongue: enlargement interferes with speech.
• Esophagus: dysphagia.
• Intestine: lesions lead to obstruction, bleeding, and perforation.
• Skin: deposits cause purpura.
• Nerve: peripheral neuropathy.
• The liver, spleen, lungs, and endocrine organs are affected less
frequently.
 Reactive Systemic Amyloidosis
• Common type of generalized (systemic) amyloid disease.
• Called secondary amyloidosis because it is secondary (sequel
or complication) to associated inflammatory conditions:
chronic pulmonary tuberculosis, lepromatous leprosy, chronic
oteomyelitis, bronchiectasis, rheumatoid arthritis, and
malignant diseases (e.g., clear cell carcinoma of the kidney and
Hodgkin’s lymphoma).
• The fibrils consists of amyloid A (AA), derived from SAA, which
is an apolipoprotein of a high-density lipoprotein and is greatly
elevated in the acute-phase reaction.
• Amyloid deposits are generally widely distributed, affecting
kidney, liver, spleen, lymph nodes and intestine.
Hemodialysis – Heredofamilial
Associated Amyloidosis Amyloidosis
• Found in patients on • Consist of a large
long-term hemodialysis number of syndromes
for renal failure. (most of them are
• The deposited material extremely rare): e.g.
is β2-microglobulun, familial amyloid
which is found in high polyneuropathy, and
concentration in amyloid nephropathy in
patient’s serum. familial mediterranean
fever.
• Amyloid deposit is
found in synovium,
joints, and tendon.
 Localized Amyloid Deposits
Endocrine associated:
• Amyloid deposits in the stroma of medullary thyroid carcinoma, a C-
cell tumor; amyloid is derived from a polypeptide hormone calcitonin.
• Amyloid deposits in the stroma of islet cell tumors, particularly those
producing insulin (amyloid is produced by proteolysis of insulin or its
prohormone).
Senile amyloidosis:
• Deposits are common in the aged (seventies and eighties); found in
heart (atria affected more frequently than ventricles) and brain (as
senile plaques).
• The plaques found in Alzheimers disease is derived from β-amyloid
protein (Aβ), derived from a glycoprotein called amyloid precursor
protein (APP).
Other localized deposits: Microscopic deposits to nodular
masses in sites such as lung, larynx, skin, bladder, and tongue.
Consist of AL protein in most cases.
 Specific Organ Involvement in Amyloid
Disease
• Kidney
• Liver
• Spleen
• Heart
• Lymph nodes
• Adrenal
• Thyroid
• Pituitary
• Gastrointestinal tract
• Respiratory tract
 Kidney in Amyloidosis
Gross: The organ is usually
enlarged and pale but a small
scarred kidney results in long
standing cases due to
secondary ischemic changes.

Micro: Amyloid is deposited

primarily in the glomeruli.
Mesengial deposition and the
deposits along basement
membrane cause capillary
narrowing and distortion of
glomerular tuft. The arterioles,
and interstitial tissue between
the tubules are also affected.
 Kidney in Amyloidosis

Clinical impact:
Renal involvement in
amyloidosis is most
common and result is
nephrotic syndrome,
often as the
presenting feature. It
is the most serious
manifestation and
major cause of death.
 Liver in Amyloidosis
Gross: Liver is enlarged,
heavy, pale, and firm.
Micro: Amyloid is deposited in
the space of Disse between the
endothelium and the liver cells,
and progressively encroaches
on adjacent hepatocytes and
sinusoids. The liver cells
undergo atrophy. Vascular
involvement and Kupffer cell
depositions are frequent.
Clinical impact: Liver
function is preserved in the
presence of marked
involvement.
 Spleen in Amyloidosis

Gross: Spleen is enlarged and firm. Focal distribution is common.

The cut surface shows numerous translucent nodules distributed
throughout the red pulp (characteristic appearance, called ‘sago
spleen’). A diffuse type is also recognized.
Micro: In localized type amyloid is laid down in the walls of the
arterioles in the white pulp and subsequently replaces the malpighian
bodies. In diffuse type, amyloid is laid down in the walls of the
sinuses and tends to spare the follicles. Fusion of early deposits lead
to large map-like areas of amyloidosis (lardaceous spleen).
 Heart in Amyloidosis
Cardiac involvement is the major
manifestation of primary
amyloidosis. It occurs in multiple
myeloma and usually in elderly
people.
Gross: Heart is enlarged, rigid, and
firm.
Micro: Begin with focal
subendocardial deposition. In due
course widespread deposition of
amyloid in the walls of blood
vessels and in the interstitial tissue
surrounding and replacing muscle
fibers.
Clinical impact: Cardiomegaly with intractable heart failure. Heart block
and arrhythmia due to involvement of conduction system are common.
Condition mimicking constrictive pericarditis due to rigidity of the muscle.
Diagnosis of Amyloid Disease in Life
• Amyloid may be demonstrated in biopsy material obtained from liver,
spleen, kidney, intestine, and bone marrow. Most common site of
biopsy is kidney, when renal manfestations are present.
• Tissue involved by amyloidosis has a tendency to bleed when
subjected to trauma. Biopsy of gingiva and rectal mucosa has
advantage over other sites in that, and should hemorrhage occur, it
can readily be controlled.
• Fine needle aspiration biopsy of the abdominal fat is also an easily
followed and extemely useful procedure for detection of systemic
amyloidosis.
• Appearance in routine stains: With light microscope and standard
tissue stains, amyloid appears as an amorphous, eosinophilic,
hyaline, extracellular substance.
• Appearance by special stain (Congo red): Amyloid stains an orange
red color under ordinary light but when the stained slide is viewed in a
polarizing microscope, a characteristic green birefringence is
imparted.
• Other investigations: In immunocyte-associated amyloidosis, serum
and urine protein electrophoresis, and immunoelectrophoresis. Bone
marrow aspiration for plasmacytosis.
Congo Red Staining of Liver in Amyloidosis
 The Nature of Amyloid
• Physical Nature:
• Electron microscopy: Amyloid material contains two components.
(1) Rigid nonbranching fibrils* (7.5 to 10 nm): Constitute the major
component (about 90%) (2) Pentagonal rod shaped sub-unit (P
components): Forms 10% of amyloid tissue and is a glycoprotein
(variable PAS positive staining).
• X-ray diffraction analysis: Characteristic β-pleated configuration* in
both major subtypes of amyloid.
• Chemical nature:
• Peptide mapping analysis of the sequence of amino acids: Of
the 15 biochemically distinct forms identified, 3 are major
chemical types of amyloid: (1) Amyloid of light chain origin (AL) from
plasma cells, (2) Unique nonimmunoglobulin protein synthesized in
the liver (AA), (3) Aβ amyloid in cerebral lesion of Alzheimer disease
• *responsible for unique staining and biological properties (e. g.,
orange red staining under ordinary light and apple green birefringence
while examined under polarized light after Congo red staining).
 The Nature of Amyloid

Structure of an amyloid fibril

Ultrastructure
 Pathogenesis of Amyloidosis
• Amyloid fibrils (AL protein or AA protein) formed in vivo from a
variety of polypeptide fragments, derived either from
immunoglobulin of plasma cell origin or from other protein
(SAA) of hepatocytic origin.
• Amyloidogenic proteins (Immunoglobulin light chains or SAA)
present in the blood is deposited in various sites following
limited proteolysis by the action of monocyte-derived enzymes.
• Thus, mononuclear phagocyte system may play a role by taking
up immunoglobulins, Ag-Ab complexes, or other proteins and
produce necessary polypeptides for formation of amyloid
fibrils.
Proposed Scheme of Pathogenesis of Two
Major Forms of Amyloid Fibrils
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