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1. AMYLOIDOSIS
DR.MULLAPUDI RAMAKRISHNA

2. DEFINITION OF AMYLOID AND
AMYLOIDOSIS
• Amyloid is defined as in vivo deposited material distinguished by the
following:
• Fibrillar appearance on electron micrography
• Amorphous eosinophilic appearance on hematoxylin and eosin staining
(see first image below)
• Beta-pleated sheet structure as observed by x-ray diffraction pattern
• Apple-green birefringence on Congo red histological staining (see second
image below)
• Solubility in water and buffers of low ionic strength

3. •Congo Amorphous eosinophilic interstitial amyloid
observed on a renal biopsy.

4. RED STAINING OF A CARDIAC BIOPSY
SPECIMEN CONTAINING AMYLOID,
VIEWED UNDER POLARIZED LIGHT.

5. • All types of amyloid consist of one major fibrillar protein that
defines the type of amyloid.
• Polymorphisms that slightly vary native peptides or
inflammatory processes set the stage for abnormal protein
folding and amyloid fibril deposition

6. AMYLOIDOSIS IS A CLINICAL
DISORDER
• caused by extracellular and/or intracellular deposition of insoluble abnormal
amyloid fibrils that alter the normal function of tissues.
• Only 10% of amyloidosis deposits consist of components such as
glycosaminoglycans (GAGs), apolipoprotein-E (apoE), and serum amyloid P-
component (SAP),
• while nearly 90% of the deposits consist of amyloid fibrils that are formed by
the aggregation of misfolded proteins.
• These proteins either arise from proteins expressed by cells at the deposition
site (localized), or they precipitate systemically after production at a local site
(systemic

7. MANY MECHANISMS OF PROTEIN
FUNCTION CONTRIBUTE TO
AMYLOIDOGENESIS,
• including “nonphysiologic proteolysis,
• defective or
• absent physiologic proteolysis,
• mutations involving changes in thermodynamic or kinetic
properties,
• and pathways that are yet to be defined.”

8. CLASSIFICATION SYSTEMS:
• Historical (Clinical Based)
• and Modern (Biochemical Based)

9. HISTORICAL CLASSIFICATION
SYSTEMS (CLINICAL BASED)
• Until the early 1970s, the idea of a single amyloid substance
predominated.
• Various descriptive classification systems were proposed based on
the organ distribution of amyloid deposits and clinical findings.
• Most classification systems included primary (ie, in the sense of
idiopathic) amyloidosis, in which no associated clinical condition
was identified, and secondary amyloidosis, which is associated
with chronic inflammatory conditions.
• Some classification systems included myeloma-associated,
familial, and localized amyloidosis.

10. • The modern era of amyloidosis classification began in the late
1960s with the development of methods to solubilize amyloid
fibrils.
• These methods permitted chemical amyloid studies.

11. MODERN AMYLOIDOSIS CLASSIFICATION
(BIOCHEMICAL BASED)
• Amyloid is now classified chemically. The amyloidoses are referred to
with a capital A (for amyloid) followed by an abbreviation for the fibril
protein.
• For example, in most cases formerly called primary amyloidosis and
in myeloma-associated amyloidosis, the fibril protein is an
immunoglobulin light chain or light chain fragment (abbreviated L);
• thus, patients with these amyloidoses are now said to have light
chain amyloidosis (AL).
• Names like AL describe the protein (light chain), but not necessarily
the clinical phenotype.

12. SIMILARLY, IN MOST CASES
PREVIOUSLY TERMED SENILE CARDIAC
AMYLOIDOSIS
• and in many cases previously termed familial amyloid polyneuropathy (FAP),
the fibrils consist of the transport protein transthyretin (TTR); these diseases
are now collectively termed ATTR.
• The major types of human amyloid are outlined and discussed individually in
the Table below.
• Great importance is now placed on appropriate and timely typing and
classification of each type of amyloid-related disease, to focus therapy and
plan appropriate monitoring.
• The common clinical amyloid entities are AL, AA, ATTR, and Aβ2M types.

13. TABLE. HUMAN AMYLOIDOSES
Type Fibril Protein Main Clinical Settings
Systemic
Immunoglobulin light chains Plasma cell disorders
Transthyretin
Familial amyloidosis, senile cardiac
amyloidosis
A amyloidosis
Inflammation-associated
amyloidosis, familial Mediterranean fever
Beta2 -microglobulin Dialysis-associated amyloidosis
Immunoglobulin heavy chains Systemic amyloidosis
Hereditary
Fibrinogen alpha chain Familial systemic amyloidosis
Apolipoprotein AI Familial systemic amyloidosis
Apolipoprotein AII Familial systemic amyloidosis
Lysozyme Familial systemic amyloidosis

14. Central nervous system
Beta protein precursor
Alzheimer syndrome, Down
syndrome, hereditary cerebral hemorrhage
with amyloidosis (Dutch)
Prion protein
Creutzfeldt-Jakob disease, Gerstmann-
Sträussler-Scheinker disease, fatal familial
insomnia, kuru
Cystatin C
Hereditary cerebral hemorrhage with
amyloidosis (Icelandic)
ABri precursor protein Familial dementia (British)
ADan precursor protein Familial dementia (Danish)
Ocular
Gelsolin Familial amyloidosis (Finnish)
Lactoferrin Familial corneal amyloidosis
Keratoepithelin Familial corneal dystrophies
Localized
Calcitonin Medullary thyroid carcinoma
Amylin* Insulinoma, type 2 diabetes
Atrial natriuretic factor
amyloidosis
Isolated atrial amyloidosis
Prolactin Pituitary amyloid
Keratin Cutaneous amyloidosis
Medin Aortic amyloidosis in elderly people
*Islet amyloid polypeptide amyloidosis.

15. A AMYLOIDOSIS (AA)
• The precursor protein is a normal-sequence apo-SAA (serum
amyloid A protein) now called "A", which is an acute phase
reactant produced mainly in the liver in response to multiple
cytokines.
• "A" protein circulates in the serum bound to high-density
lipoprotein.
• AA occurs in various chronic inflammatory disorders, chronic local
or systemic microbial infections, and occasionally with neoplasms.
• The frequency of amyloidosis has been shown to vary significantly
in different ethnic groups.

16. • Typical organs involved include the kidney, liver, and spleen.
Worldwide, AA is the most common systemic amyloidosis; it was
formerly termed secondary amyloidosis.
• Therapy has traditionally been aimed at the underlying
inflammatory condition to reduce the production of the precursor
amyloid protein SAA.
• Disease-modifying antirheumatic drugs (DMARDs) like colchicine,
a microtubule inhibitor and weak immunosuppressant, can
prevent secondary renal failure due to amyloid deposition
specifically in familial Mediterranean fever.

17. NEWER THERAPIES
• have become more targeted to avoid the cytotoxicity of older
agents (chlorambucil, cyclophosphamide).
• The SAA amyloid seen in CAPS was reduced with a biologic
interleukin (IL)–1β trap called rilonacept. Tumor necrosis factor-
alpha (TNF-alpha) is also thought to be involved in amyloid
deposition.
• Aggressive use of newer biologic therapies for RA, such as
etanercept (a TNF-alpha blocker), and tocilizumab have been
used to decrease the concentration of SAA, serum creatinine,
creatinine clearance, and proteinuria in renal AA associated with
RA

18. LIGHT CHAIN AMYLOIDOSIS (AL)
• The precursor protein is a clonal immunoglobulin light chain
or light chain fragment. AL is a monoclonal plasma cell
disorder closely related to multiple myeloma, as some patients
fulfill diagnostic criteria for multiple myeloma.
•
• Typical organs involved include the heart, kidney, peripheral
nerve, gastrointestinal tract, respiratory tract, and nearly any
other organ. AL includes former designations of primary
amyloidosis and myeloma-associated amyloidosis.

19. • Treatment usually mirrors the management of multiple
myeloma (ie, chemotherapy).
• Selected patients have received benefit from high-dose
melphalan and autologous stem-cell transplantation, with
reports of prolonged survival in recent studies.
• Alternative therapeutic approaches include thalidomide,
lenalidomide, iododoxorubicin, etanercept, and rituximab.

20. THE MOST CURRENT GUIDELINES
RECOMMEND HIGH-DOSE
• steroids for isolated organ involvement, but transplantation
should be considered early.
• Any transplantation should also be followed by high-dose
intravenous melphalan supported with stem-cell transplantation
to try to prevent future amyloid deposition in the transplanted
organ.
• Patients younger than 65 years may be candidates for a stem cell
transplantation with melphalan and dexamethasone or
thalidomide-cyclophosphamide-dexamethasone regimens.

21. HEAVY CHAIN AMYLOIDOSIS (AH)
• In a few cases, immunoglobulin chain amyloidosis fibrils
contain only heavy-chain sequences rather than light-chain
sequences, and the disease is termed AH rather than AL.
• Electron microscopy may be helpful in the detection of small
deposits and in the differentiation of amyloid from other types
of renal fibrillar deposits.

22. TRANSTHYRETIN AMYLOIDOSIS
• The precursor protein is the normal- or mutant-sequence
transport protein transthyretin (TTR), a transport protein
synthesized in the liver and choroid plexus
• this disease was also termed senile cardiac amyloidosis. The
prevalence of TTR cardiac amyloidosis increases progressively
with age, affecting 25% or more of the population older than 90
years.
• Treatment for mutant-sequence amyloidogenic TTR is liver
transplantation or supportive care.
• Tafamidis is also an effective agent to slow the progression of
peripheral neuropathy. For normal-sequence
amyloidogenic TTR, the treatment is supportive care.

23. BETA2-MICROGLOBULIN AMYLOIDOSIS
( ABETA2M)
• β2 M is normally catabolized in the kidney after it is displaced
from the MHC-I heavy chain in the proximal tubules, but in
patients with decreased clearance the serum level of the β2 M can
be more than 60 times the normal level.
• In patients with renal failure, the protein accumulates in the
serum, leading to secondary osteoarticular destruction and
dialysis-related amyloidosis (DRA).
• Treatment also includes renal transplantation, which may arrest
amyloid progression.

24. HEREDITARY RENAL AMYLOIDOSES
• Hereditary amyloidoses encompass a group of conditions that
each are related to mutations in a specific protein.
• The most common form is transthyretin amyloidosis (usually
neuropathic), but non-neuropathic amyloidoses are likely the
result of abnormalities in lysozyme, fibrinogen, alpha-chain, or
apolipoprotein A-I and A-II.
• A clinical correlation is required to diagnose amyloid types, even
if a hereditary form is detected by amyloid protein typing.

25. APPROACH TO DIAGNOSING
AMYLOIDOSIS
• Pathologic diagnosis (Congo red staining and immunohistochemistry)
• Immunocytochemical studies for amyloid should include stains for
Congo Red (apple-green birefringence), hematoxylin and eosin stains
for amorphous material, kappa and lambda light chains, beta-
amyloid A4 protein, transthyretin, beta 2-microglobulin, cystatin C,
gelsolin, and immunoreactivity with antiamyloid AA antibody.
• Amyloidosis is diagnosed when Congo red–binding material is
demonstrated in a biopsy specimen. Because different types of
amyloidosis require different approaches to treatment, determining
only that a patient has a diagnosis of amyloidosis is no longer
adequate.

26. • A clinical situation may suggest the type of amyloidosis, but the
diagnosis generally must be confirmed by immunostaining a
biopsy specimen.
• New adjuncts to traditional laboratory testing are now available.
The serum free light chain test is commercially available and can
aid in screening, diagnosis, prognosis, and treatment monitoring
by detecting detects low concentrations of free light chains and
can measure the ratio of kappa chains to lambda chains.

27. IMAGING
• Several modalities can help visualize amyloid deposits. Cardiac
amyloidosis can be visualized with gated MRI and technetium
pyrophosphate (99m Tc-PYP) scintography.
• In some cases, scintography can distinguish AL from ATTR
cardiac amyloidosis.
• Imaging techniques such as structural MRI and
fluorodeoxyglucose (FDG) positron emission tomography (PET)
can show structure and function pathology longitudinally, but "the
extent and topographical distribution of Aβ deposition correlates
relatively poorly with cognitive profile, severity or progression of
the clinical deficit."

28. TREATMENT OF AMYLOIDOSIS
• Doxycycline
• Using a low dose of 100 mg of doxycycline daily, they were able
to provide pain reduction, increased range of motion, and no
adverse effects at 5 months.
• Beta-2m-adsorbing columns for dialysis
• β2-m–adsorbing columns have demonstrated some benefit in
dialysis-related amyloidosis. This addition to long-term
dialysis may reduce inflammation and accumulation of fibrils
without major adverse effects

29. IMMUNOTHERAPY
• Aβ immunotherapies have shown some promise in the treatment of
Alzheimer disease. Agents with great potential include the passive
monoclonal antibodies bapineuzumab and solanezumab. However,
both of these humanized monoclonal antibodies have failed to provide
meaningful cognitive changes in clinical trials. Further studies using
this strategy are ongoing.
• Gantenerumab
• Gantenerumab is the first fully human monoclonal antibody that
binds regions of Aβ configuration not present in the structure of the
native monomeric Aβ. Therefore, gantenerumab preferentially binds
to aggregated Aβ.[
• Tafamidis

30. TREATMENT RESPONSE IN
AMYLOIDOSIS
• While amyloidosis is a very heterogeneous disease, there has been a
focused effort to define what a meaningful response to therapy looks
like. Each effected organ can be measured over time.
• In cardiac amyloidosis, improvement is defined by a “mean
interventricular septal thickness decreased by 2 mm, 20%
improvement in ejection fraction,
• improvement by 2 NYHA classes without an increase in diuretic use,
and no increase in wall thickness and/or a reduction (≥ 30% and ≥ 300
ng/L) of NT-proBNP in patients in whom the eGFR is ≥ 45
mL/min/1.73 m2“.

31. FOR RENAL-RELATED
AMYLOIDOSIS
• a meaningful clinic response is defined as "50% decrease (at
least 0.5 g/day) of 24-hr urine protein (urine protein must be >
0.5 g/day pre-treatment) in the absence of a reduction in eGFR
≥ 25% or an increase in serum creatinine ≥ 0.5 mg/dL".
• For liver-related amyloid, a drop in the size of the liver by 2
cm radiographically and a 50% drop in the alkaline
phosphatase level is a meaningful clinical response goal.

32. SUPPORTIVE CARE
• Symptomatic care in A. is paramount, given the limited targeted
therapeutics. Certain organ-specific types of amyloid are beginning to
have standards of supportive care.
• For example, cardiac A. requires judicious use of rate and rhythm
control agents to prevent fatal arrhythmias. Amyloid can infiltrate
the conduction system and the coronary arteries.
• In addition higher doses of ACEi can also foster dangerous
hypotension and are not recommended.
• Beta-blockers are relatively contraindicated in cardiac A. and are
associated with a higher death rate.
• Amiodarone (200 mg PO q5d/wk), however, prevents arrhythmias
and should be considered first and continued indefinitely.[109]

33. VERY GENTLE PRELOAD REDUCTION
• with diuretics is important to decrease the effects of restrictive
pathology and higher filling pressures, but orthostasis is common
and dangerous.
• Attempting to make peripheral edema disappear with diuretics is
not advised and can cause dangerously low cardiac output.
• Defibrillators may be a life-saving option for fatal arrhythmias,
but there are not great data indicating they prevent mortality.
• Even so, pacemakers may still have a role in preventing
symptomatic bradycardia or conduction blocks.