Amyloidosis for the young
ladies
Amyloidosis
Definition : In medicine, amyloidosis refers to a variety of
conditions in which amyloid proteins are abnormally
deposited in organs causing disease. A protein is amyloid
if, due to an alteration in its secondary structure, it takes on
a particular insoluble form, called the beta-pleated sheet.
AMYLOIDOSIS
• Disease characterized by extracellular deposition of
pathologic insoluble fibrillar proteins in organs and
tissues.
• Term amyloid first coined by Virchow in mid 19th
century (meaning starch or cellulose).
• Amyloid found to stain with congo red, appearing
red microscopically in normal light but apple green
when viewed in polarized light.
• Fibrillar nature and beta pleated sheet configuration
described by electron microscopy in 1959.
Amyloidoses Are Protein Misfolding
Diseases
Binding sites for Congo red
Protein Misfolding Diseases

A specific protein may be unable to carry out its normal function
because it is improperly folded or because it is not sufficiently stable
due to misfolding.

A protein may be unable to carry out its normal function because it is
not trafficked to the proper location due to misfolding.

A protein may fail to fold or to remain folded correctly and
consequently aggregate (often with other components) leading to
amyloid diseases. (“Amyloidosis” refers strictly to diseases in which
extracellular deposits are formed, but the terms “amyloid diseases” or
“protein aggregation diseases” are now being used to refer to
diseases in which protein deposits are intra- or extracellular.)

Some of the clinical symptoms of the non-neurological amyloidoses
seem to be due to the accumulation of large deposits of aggregated
proteins in vital organs

In neurodegenerative diseases, cellular function appears to be
impaired by the interaction of aggregated proteins with cellular
components. This impairment is associate with evidence of elevated
oxidative stress, but the mechanism is unknown.
Pathogenesis of the major forms of amyloid fibrils
Systemic amyloidoses are those which affect more than one
body organ or system.
Localised amyloidoses affect only one body organ or tissue type.
Primary amyloidoses arise from a disease with disordered
immune cell function such as multiple myeloma and other
immunocyte dyscrasias.
Secondary (reactive) amyloidoses are those occurring as a
complication of some other chronic inflammatory or tissue
destructive disease.
• Imaging techniques – Technetium Tc 99m
pyrophosphate binds avidly to many types of
amyloid. Quantitative assessment not possible
and strongly positive results usually only
occur in pt’s with severe disease. Technetium
labeled aprotinin may be more sensitive.
• Quantitative scintigraphy can be done with
iodine-123- labeled serum amyloid P
component (sensitive for AL, ATTR and AA
amyloid).
Multiple Myeloma: Incidence and
Etiology
• 13,000 cases/year in USA
• Median age - 65 yrs.
• Incidence in African-Americans is two-fold
other ethnic groups
• Familiar clusters are rare
• Environmental/occupational exposures have
been implicated
AL AMYLOIDOSIS
• Part of the spectrum of plasma cell dyscrasias.
• Cellular source of AL amyloid is always a
single clone of the B-lymphocytic lineage,
usually exhibiting the morphologic
appearance of plasma cells.
• Underlying clonal proliferative disorder may
be frankly neoplastic (ie:multiple myeloma) or
conversely a low grade proliferation of
monoclonal plasma cells.
Macroglossia
hoarsenes
Heart failure
Autonomic nervous
system involvement
Carpal tunnel sy
Peripheral nervous
system involvement
Thrombocytosis
AL AMYLOID
Splenomegaly
Anemia
Hypofunction
of adrenal glands
hypothyreosis
Hepatomegaly
Nephrotic syndrome
• Among MM patients, amyloidosis reported
with variable frequency, but rarely exceeds
20%.
• Majority of patients without myeloma
associated AL, occurs in the setting of an
apparently “benign” monoclonal
gammopathy.
• Characterized by low concentrations of
monoclonal Ig’s in serum/urine and an often
occult low grade monoclonal plasma cell
proliferation in BM.
Bone marrow aspirate: Plasma cell infiltrate
AL Amyloidosis
IF anti l
Kidney (74%)
Heart (58%)
Bone marrow plasma cell clone
synthesizing amyloidogenic light chain
No of organs involved:
1 (31%)
>1 (69%)
Liver (28%)
GI (8%)
Primary Amyloidosis: Histopathology
Conditions Associated With
AA Amyloidosis
Chronic Inflammatory
Diseases
Rheumatoid arthritis
Psoriatic arthritis
Chronic juvenile arthritis
Ankylosing spondylitis
Behcet’s syndrome
Reiter’s syndrome
Adult Still's disease
Chronic Infections
Tuberculosis
Osteomyelitis
Bronchiectasis
Leprosy
Pyelonephritis
Decubitus ulcers
Whipple’s disease
Acne conglobata
Inflammatory bowel disease
Hereditary periodic fevers
Common variable
immunodeficiency
Hypo/agammaglobulinemia
Cystic fibrosis
Neoplasia
Hepatoma
Renal carcinoma
Castleman's disease
Hodgkin's disease
Adult hairy cell leukemia
Waldenström's disease
Presenting Clinical Features
in AA Amyloidosis
Feature
%
Proteinuria/renal insufficiency
91
Diarrhea/malabsorption
22
Goiter
9
Neuropathy/carpal tunnel syndrome
3
Hepatomegaly
5
Lymphadenopathy
2
Cardiac
1 -2
• Macroglossia – occurs in 10-20 %
• Amyloid can be found within any part of the
GI tact and may infiltrate parenchyma, organs
and nerves.
• Peripheral neuropathy may be presenting
manifestation or develop subsequently during
the course of the illness (history of carpal
tunnel frequently elicited).
• Neuropathy usually distal, symmetric and
progressive. Cranial nerve and autonomic
nerve involvement also well described.
• Motor neuropathy rare.
Macroglossia
Purpura
HEPATIC/SPLENIC
• Involvement of liver common.
• Hepatomegaly may be striking at presentation and
usually disproportionate to extent of liver enzyme
abnormalities (except alkaline phosphatase which is
frequently elevated).
• Presence of jaundice is an adverse prognostic factor
and MST from onset of jaundice is only 3 months.
• Patients may present with severe intrahepatic
cholestasis.
• Massive splenic deposition may result in functional
hyposplenism.
Extensive hypertrophy with yellow amyloid
deposits
CARDIAC
• May present with rapid and progressive onset
of CHF.
• Characteristically, features are predominantly
of right sided CHF.
• ECG – low voltage and may have a pattern of
MI in absence of CAD.
• ECHO – concentrically thickened ventricles
with normal-small cavity and diastolic
dysfunction on doppler.
• Clinical clue is marked worsening of failure
when CCB used.
Echocardiogram revealing thickened walls with
small chambers
RENAL
• Nephrotic syndrome present in 30-50% at
diagnosis.
• Nephrotic syndrome and renal failure develop
only rarely during course of the illness if not
present at time of diagnosis.
• λ BJP have been associated with inferior
survival as compared with κBJP or no
monoclonal protein, irrespective of serum
creatinine.
Lambda
Kappa
• AL arthropathy – may simulate RA. Most
striking appearance is the ‘shoulder pad sign’
secondary to swelling of the shoulder joints.
• Vascular infiltration may result in easy
bruising especially in the eyelids and flexural
regions. Purpuric lesions typically occur above
the nipple.
• Factor X deficiency (acquired) can occur in up
to 10% of pt’s and over 2/3 of pt’s with
acquired factor X deficiency have systemic
Amyloidosis.
Amyloidosis
Heart
This islet of Langerhans demonstrates pink hyalinization (with deposition of amyloid) in
many of the islet cells. This change is common in the islets of patients with type II
diabetes mellitus.
PROGNOSIS
• Serious disease with high mortality.
• Overall median survival after diagnosis is < 2years in
most series.
• Patients with co-existent MM have a poorer
prognosis.
• Survival time largely dependent upon the organ
system predominantly involved.
• Cardiac involvement is major determinant of
prognosis and most common cause of death – MST
from onset of CHF is 7 months.
• Results of a a large trial of 220 pts by Kyle et al in
1997 clarified the role of colchicine in AL
Amyloidosis.
• Median duration of survival was 8months for the C
group, 18 months for the MP group and 17 months
for the MPC group.
• Median survival for pts with cardiac amyloid was 5
months, 16 months for pts with renal involvement
and 34 months for those with PN. Survival was best
in those patients showing a 50% reduction in serum
or urine paraprotein levels.
CONCLUSIONS
• Systemic, uncommon disease with poor long term
survival.
• Symptoms often vague and recognition of syndromes
associated with amyloidosis is key.
• In general, current therapy is suboptimal although
new treatment options including thalidomide,
proteosome inhibitors, antisense oligonucleotides
and SCT hold promise for the future.