A Powerpoint presentation on the epidemiology, etiology, pathogenesis, clinical features, diagnostic work up and treatment of the common types of amyloid.

1. AMYLOIDOSIS
A presentation by
Dr Charles C. Ntima
Department of Internal Medicine
BSUTH

2. AMYLOIDOSIS: OUTLINE
 Introduction
 Classification
 Epidemiology
 Risk Factors
 Aetiology
 Pathophysiology
 Clinical features/ Complications
 Investigations
 Treatment
 Prognosis
 Conclusion

3. AMYLOIDOSIS:
INTRODUCTION
• Amyloidosis is the term used for diseases
caused by the deposition of insoluble
polymeric protein (amyloid) fibrils in tissues
and organs.
• Deposition of amyloid fibrils is usually
extracellular.
• These deposits alter the normal function of
the tissues in which they accumulate.

4. AMYLOIDOSIS: CLASSIFICATION
• Various classification methods have
evolved over time.
• Earlier classification models were based
on organ distribution of amyloid
deposits as well as clinical findings.
• Later classification models are based on
the type of amyloid protein implicated in
the disease process.

5. AMYLOIDOSIS: CLASSIFICATION
HISTORICAL CLASSIFICATION
• Classification based on organ distribution:
- Systemic amyloidosis (affecting ˃ 1
organ or tissue type)
- Localised amyloidosis (affects only
one organ or tissue type)

6. AMYLOIDOSIS: CLASSIFICATION
HISTORICAL CLASSIFICATION
• Classification based on associated clinical
findings:
- Primary (Idiopathic) amyloidoses: in which no
associated clinical condition is identified with the
disease process.
- Secondary (Reactive) amyloidoses: usually
associated with chronic inflammatory conditions.

7. AMYLOIDOSIS: CLASSIFICATION
MODERN CLASSIFICATION
• Based on the chemical composition of
the deposited amyloid protein and not
neccesarily on the clinical phenotype.
• This method employs the use of an
abbreviative system whereby the
amyloidoses are referred to with a capital
“A” (for amyloid) followed by an
abbreviation for the fibril protein eg AL, AA

8. AMYLOIDOSIS: MODERN CLASSIFICATION
OFFICIAL ABBREVIATION AMYLOID TYPE/GENE DESCRIPTION
AL Amyloid light chain (λ) AL amyloidosis/ Multiple myeloma
AA Serum amyloid A protein AA amyloidosis
Aβ β amyloid Alzheimer’s disease
Aβ2M β2 amyloid microglobulin Hemodialysis related amyloid
ALect2 LECT2 protein LECT2 amyloidosis
ATTR Transthyretin Familial amyloid polyneuropathies, Wild
type transthyretin amyloidosis,
leptomeningeal amyloidosis
AIAPP amylin Type II diabetes
APrP prion protein CJD, BSE
ACys CST3 Cerebral Amyloid Angiopathy
AGel GSN Finnish type amyloidosis
AApoA1¹/ Afib²/ Alys³ APOA1¹/ FGA²/LYZ³ Familial visceral amyloidosis
APro prolactin Prolactinoma
AKer keratoepithilin Familial corneal amyloidosis
AANF Atrial natriuretic factor Senile amyloid of the heart
ACal Calcitonin Medullary carcinoma of the thyroid

9. AMYLOIDOSIS: EPIDEMIOLOGY
• A rare disease (...and thus epidemiological
studies are also rare)
• Worldwide incidence not known
• Limited data from developing countries
• Estimated annual incidence in the USA is about
8.9 new cases/ million inhabitants/yr.
• Studies in Europe have shown incidence rates
of 5.2 to 11.9 new cases/million inhabitants/yr

10. AMYLOIDOSIS: EPIDEMIOLOGY
• Data from the NIH (UK) showed that in
2002- 2003:
- amyloidosis accounted for 0.008% of
hospital consultations
- 86% of these consultations required
hospital admission
- 23% of these presented as emergencies
- mean length of hospital stay = 9.4 days

11. AMYLOIDOSIS: EPIDEMIOLOGY
• More common in the middle aged/ elderly
- median age at time of diagnosis = 64 yrs
• More common in males than in females (˃
⅔ of cases)
• Most common types are AL amyloidosis,
AA amyloidosis, and ATTR

12. AMYLOIDOSIS: EPIDEMIOLOGY
• AL amyloidosis is the most common
variation particularly in Western countries
(accounting for about 90% of cases).
• AA amyloidosis is the second most
common type worldwide but prevalence
rates are presumed to be higher in
developing countries.

13. AMYLOIDOSIS: RISK FACTORS
• Age (˃ 50 years)
• Family history (hereditary types)
• Race ( ATTR common among the Hispanic population)
• Male sex (70% of cases)
• Chronic inflammatory conditions
• Associated history of multiple myeloma (10-15% of cases)
• Long term haemodialysis
• Ingestion of amyloid fibres in meat of animals affected with the
disease

14. AMYLOIDOSIS: AETIOLOGY
• The aetiological agent involved in amyloidosis is the
pathological proteinaceous substance known as
amyloid.
• Characteristics
- Fibrillar appearance on electron microscopy
- Amorphous eosinophilic appearance on
heamatoxylin & eosin staining
- β-pleated structure seen by x-ray diffraction pattern
- Apple green birefringence on Congo red histological
staining
- Solubility in H2O and buffers of low ionic strength

15. AMYLOIDOSIS: AETIOLOGY
• Largely made up of continuous
non-branching fibrils
• Electron microscopic structure
is identical in all types of
amyloid (cross-β- sheet
conformation).
• Serum amyloid P component
and glycoproteins make up 10-
15% of mass of the amyloid
protein molecule

16. AMYLOIDOSIS: PATHOPHYSIOLOGY
• The amyloidogenic precursors may
trigger amyloid formation when
their concentration ↑es in serum or
because a mutation favors
misfolding
• Interaction with the extracellular
environment may result in
incomplete proteolytic cleavage
and binding to matrix components
such as glycosaminoglycans
(GAGs) and collagen that facilitate
aggregation
• Serum amyloid P (SAP) binds to
amyloid fibrils and protects them
from reabsorption via normal
protein scavenging mechanisms

17. AMYLOIDOSIS: PATHOPHYSIOLOGY
• Organ damage is thought to be caused by
both the oligomers as well as the amyloid
fibrils themselves.
• This damage is caused by physical /
mechanical replacement of parenchymal
tissue as well as direct cytotoxicity of the
oligomers

18. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Presentation is broad and depends on the site and
type of amyloid accumulation.
• In some tissues amyloid accumulation causes organ
enlargement.
• However, in certain other tissues amyloid deposits
cause progressive decline in organ function and
ultimatley organ failure.

19. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Clinical suspicion: unexplained
nephropathy, cardiomyopathy,
neuropathy, enteropathy, arthropathy or
macroglossia.
• The kidneys and the heart are the most
commonly involved organs

20. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Renal (33-40%):
- proteinuria ± ↑ Urea/↑SCr
- renal insufficiency a rare complication
• Cardiovascular (20-40%)
Heart:
- may present with either diastolic or systolic heart
failure. RV dysfunction more common than LV
dysfunction.
- may also cause conduction abnormalities eg
atrioventricular block, sinus node dysfunction,
low voltage complexes on the ECG.

21. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Cardiovascular
Blood vessels:
- ↑ed susceptibility to
bruising/bleeding around
the eyes (Raccoon eyes)
- caused by deposition of
amyloid in vessels around
the eyes + ↓ed activity of
Factor X and Thrombin.

22. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Macroglossia (˂ 15%) due
to accumulation of amyloid
in the tongue
- dyspnoea
- obstructive sleep apnoea
- dysphagia/dysphonia
- Sialorrhea
- Angular chelitis
- Crenated tongue
- Orthodontic abnormalities

23. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Nervous System:
Central Nervous System
- Dementia (Alzheimer’s disease, Down’s
Syndrome)
- Haemorrhagic strokes (2° to Cerebral amyloid
angiopathy)
Peripheral Nervous System
- Peripheral neuropathy
- Autonomic neuropathy eg postural
hypotension, GIT symptoms

24. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Liver:
- liver enlargement
- ↑alkaline phosphatases ± ↑ transaminases
• Spleen:
- splenic enlargement (˂ 5% of cases)
- splenic dysfunction (˃ 25% of cases)
• GIT (amyloid deposits seen in 80-90% of cases,
only 1% are symptomatic):
- malabsorption

25. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Musculoskeletal:
- “Shoulder pad sign”:
enlargement of the
anterior shoulder due
amyloid deposition in
periarticular soft tissue
- Involvement of the
synovial space may
result in chronic synovitis
(Carpal tunnel syndrome
in the wrist)

26. AMYLOIDOSIS:
CLINICAL FEATURES / COMPLICATIONS
• Endocrine organs:
- Hypothyroidism 2° to infiltration of the
thyroid gland
- Hypoadrenalism
- Type II Diabetes mellitus

27. AMYLOIDOSIS: CLINICAL FEATURES
• Skin:
- macular rash on the interscapular region
of the back (Macular amyloidosis)
- lichenoid papules appearing bilaterally on
the shins ( Lichenoid amyloidosis)
- nodules involving the acral area (nodular
amyloidosis....a rare presentation)

28. AMYLOIDOSIS: INVESTIGATIONS
• Tissue biopsy provides definitive diagnosis.
• Diagnosis rests upon the identification of
pathologic amyloid deposits as well as
immunohistochemical or biochemical
identification of amyloid type.
• In the systemic amyloidoses, the involved
organs can be biopsied, but amyloid deposits
may be found in any tissue of the body.

29. AMYLOIDOSIS: INVESTIGATIONS
• Fat Pad Biopsy: Fat, aspirated from the abdominal
wall, is the most easily accessible tissue and biopsy is
positive in ˃ 80% of patients with systemic
amyloidosis (rectum → salivary gland/gingiva →
internal organs).
• Staining of the tissue specimen with Congo Red
reveals an apple-green birefringence when viewed by
polarized light microscopy.

30. AMYLOIDOSIS: INVESTIGATIONS
• Other tests, although not diagnostic, which
may be carried out include:
- Peripheral blood film → Howell Jolly
bodies seen in hyposlenism 2° to splenic
involvement
- Acute phase reactants (ESR, CRP) →
↑↑ in AA

31. AMYLOIDOSIS: INVESTIGATIONS
- Urinalysis → proteinuria in renal amyloidosis.
- Serum protein → ↓ed in renal amyloidosis.
- Serum/urine protein electrophoresis →
presence of monoclonal light (λ) chains in AL
amyloidosis.
- Bone marrow biopsy → identification of
dominant plasma cell in AL amyloidosis.

32. AMYLOIDOSIS: INVESTIGATIONS
- BNP, pro-BNP, Troponin → ↑ed in
cardiac amyloidosis.
- ECG → Low voltage QRS complexes,
conduction blocks.
- Echocardiography → restrictive filling
pattern.
Often a “ speckled” pattern can also be
seen with an ↑ed echo signal.

33. AMYLOIDOSIS: INVESTIGATIONS
- Serum alkaline phosphatase → ↑ed with
liver involvement. Liver transaminases are
often normal or slightly ↑ed. Serum
bilirubin may also be ↑ed.
- Thyroid function test → 1° hypothyoidism

34. AMYLOIDOSIS: TREATMENT
• Amyloidosis has no cure
• Initial management should include an
assessment of the degree of organ
involvement.
• Treatment goals are two-fold:
- supportive therapy
- measures targeted at limiting further
production of amyloid protein (...where this
is possible)

35. AMYLOIDOSIS: TREATMENT
• Supportive therapy
- Patient counselling
- Pain medication
- Diuretics
- Low salt diet
- Dietary modifications especially in those
with GIT amyloid

36. AMYLOIDOSIS: TREATMENT
• Limiting further amyloid production:
Treatment approach depends on the type of
amyloidosis that is present
- treatment of the underlying disease in AA
amyloidosis
- Compounds that interfere with the binding of
glycosaminoglycans to the amyloid proteins
(eg Eprodisate) have been successful in
secondary amyloidosis

37. AMYLOIDOSIS: TREATMENT
- use of cytotoxic agents (Melphalan or
Bortezomib) + Stem cell transplantation
OR steroids in cases of AL amyloidosis
- use of immunomodulatory drugs (eg
Thalidomide, Lenalidomide) + steroids in
the treatment of some cases of AL
amyloidosis.

38. AMYLOIDOSIS: TREATMENT
- use of β2-macroglobulin adsorbing
columns, changing the mode of dialysis or
renal tranplants in patients with dialysis
related amyloidosis.
-Liver transplants may be an option in
ATTR amyloidosis,
- use of PO doxycycline (100mg od )in
amyloid arthropathy

39. AMYLOIDOSIS: TREATMENT
- Small molecules capable of stabilizing the
amyloid precursor and preventing its
misfolding and aggregation (diflunisal,
tafamidis) are being tested in ATTR
amyloidosis.
- Serum amyloid P component can be
cleared from amyloid deposits by using
small palindromic drugs (eg, CPHPC).

40. AMYLOIDOSIS: PROGNOSIS
• Prognosis varies with the type of amyloidosis.
• AL amyloidosis carries the worst prognosis if left
untreated with median survival of two years (↓es with
↑ing severity).
• Outcomes in patients with AA amyloidosis depends
on the underlying disease and symptoms may
improve if the underlying condition is treated.
• People with ATTR have the best prognosis and may
survive over a decade.
• Cause of death in most cases of amyloidosis is cardiac
failure or sudden death from a fatal arrhythmia.

41. AMYLOIDOSIS: CONCLUSION
• Amyloidosis is a chronic disorder affecting several
organs with significant associated morbidity and
mortality.
• Although it is incurable, certain types of amyloidosis
have a better prognosis than others.
• Advances in the understanding of the molecular
mechanisms involved in amyloid formation and tissue
damage have stimulated ongoing research in novel
treatment strategies.
• Diagnosis and early initiation of treatment in some cases
may improve the outcome.

42. THANK YOU
FOR LISTENING

43. References
• Harrison’s Textbook of Internal Medicine,
19th Edition
• Amyloidosis Treatment and Research Program,
Boston University School of Medicine
• JOURNAL OF CLINICAL ONCOLOGY 29,
American Society of Clinical Oncology
• 2010 recommendations from the nomenclature committee of
the International Society of Amyloidosis