Amyloidosis

Amyloidosis
DEF.:

disorder of protein
metabolism accompanied
with abnormal extracellular
deposition of proteinaceous
material - amyloid

Amyloid - history

Amyloid = starch like

Karl Freiherr von Rokitansky (1804-1878)
Rudolf Ludwig Karl Virchow (1821-1902).

Amyloid - history 2.

Karl Freiherr von Rokitansky (1804-1878)

Austrian pathologist, born February 19, 1804,
Kniggrtz, Bhmen, Austrian Empire (now
Hradec Krlov, East Bohemia, Czech Republic);
died July 23, 1878, Wien.

Handbuch der pathologischen Anatomie IInd

Band, Wien 1842

Amyloidosis morphology
Macroscopy:

small amounts invisible

larger deposits enlarged,
firm, waxy organs

Ultrastructure &
Biochemistry of Amyloid
90-95% non branched
fibrils diam. 10-12nm
5-10% p-component - glycoprotein +
fibronectin, laminin, collagen 4

Amyloidosis
conformational disease
(Carrell and Lomas, Lancet, 1997)

arises when a constituent protein

undergoes a change in size or
fluctuation in shape with resultant
self - association and tissue
deposition

pleated sheet structure

Conformational diseases
(Carrell and Lomas, Lancet, 1997)

Amyloidosis
Prionoses - transmissible

spongiform encephalopathies (incl. m.

CJD)

m. Alzheimeri
pleated sheet structure

Amyloidosis
Classification:

according to the source protein

(more than 20 different identified)

according to the distribution

systemic (generalised)
localised

Systemic Amyloidosis - I.
AL - imunocyte dyscrasia associated
light chains Ig (mostly )
primary
Distribution: tongue, heart, GIT, liver, spleen,
kidney
Associated diseases: Plasma cell myeloma,
B cell lymphoma,

Systemic Amyloidosis - II.

AA - reactive systemic amyloidosis
SAA = Serum Amyloid Associated
protein
secondary
Distribution: liver, kidney, spleen, GIT, lymph nodes,
bowel, adipose tissue
Associated diseases: rheumatoid arthritis, chronic
infections (tb, leprosy, bronchiectasiae,
osteomyelitis, IBD, neoplasms MLH , RCC

Systemic Amyloidosis - III.

senile systemic SSA
25% people over the age of 80 years (!)
-normal transthyretin TTR (prealbumin)
-mostly

heart & vessels invilvement

Systemic Amyloidosis - IV.

A2 - hemodialysis associated
2 microglobulin

Hereditary
AA
- Familial Mediterranean Fever
ATTR - Famil. polyneuropatia
transthyretin (mutated form)

Systemic Amyloidosis - complications

diminished functions of some organs, esp.

KIDNEY FAILURE
IIIrd stage Amyloid nephrosis

Localised Amyloidosis - I.
Senile cardial
ATTR - transthyretin (structurally normal)

Senile cerebral
A

- -amyloid

protein

Cardiac Amyloidosis clinical manifestations

Dilated Cardiomyopathy

Congestive heart failure

Rhytm abnormalities
Coronary insufficiency
Valvular dysfunction
Pericardial tamponade
Enhance sensitivity to digitalis glycosides
Atrial thrombosis - embolisation

(predominant systolic
dysfunction)
Restrictive cardiomyopathy
(predominant diastolic
dysfunction)

Localised Amyloidosis - II.

Endocrine
ACal - ca medullare gl. thyreoideae
AIAPP - islets of Langerhans associated
AANF - isolated atrial amyloidosis
atrial natriuretic polypeptide

Nodular tumoriform amyloid deposits

(tongue, lung,larynx, skin, urinary bladder, orbita)

Clinical Diagnosis of Amyloid

Scintigraphy (in vivo)
using human serum amyloid component
marked with 123J

Echocardiography
(atrial amyloid)

Clinical Diagnosis of Amyloid

Biochemistry
sequening DNA -hered. forms
extraction of fibrils (from a biopsy
spectrometry
sequening of the amyloid protein

specimen)

Amyloidosis morphology
Macroscopy:

small amounts invisible

larger deposits enlarged,
firm, waxy organs

Morphological
Diagnosis of Amyloid
Macroscopy

reaction Virchow I
Virchow II

(sol. Lugolli)

(H2SO4)

Morphological
Diagnosis of Amyloid
Microscopy:

KONGO red
(+POLARISATION!) + KMnO4
thioflavine S,T
crystal. violet (metachromasia)
IMMUNOHISTOCHEMISTRY
(electron microscopy)

Morphological Diagnosis of Amyloid

Materials:
GIT (stomach, duodenum rectum, gingiva)
biopsy
kidney
sural nerve & muscle
fat aspiration biopsy needle with an internal
diam. 0,7-1,2mm
Rcken Ch. Sletten K.: Amyloid in Surgical Pathology
Virchows Arch., 2003, 1-26

CONGO Red
synthesized by young chemist at Bayer comp. 1883 as
the first of economically lucrative direct (nod needing a
mordant) textile dyes
patented by AGFA 1885
(Aktiengeselschaft fr Anilinfarbenfabrikation)
3 weeks after the conclusion of the
West Africa Conference
to Europeans in 1885, the word Congo evoked exotic
images of far-off central Africa known as The Dark
Continent
the Congo red stain was named Congo for marketing
purposes by a German textile dyestuff company in 1885

Steensma DP: Congo Red. Out of Africa? Arch. Pathol.Lab.Med.,2001, 125, 250-2

Reversibility of Amyloid

The deposits are NOT irreversible.

e.g. Hrncic R. et al: Antibody mediated resolution of
light chain associated amyloid deposits. Am.J.
Pathol., 2000, 157,12369-46

Progression of generalised amyloidosis

can be delayed or stopped by treatment
of the underlying disease.
Rcken Ch. Shakespeare Ann: Pathology, diagnosis
and pathogenesis of AA amyloidosis. Virchws Arch. ,
2002, 440, 11-122

Prevention & Therapy of Amyloid

Prevention & treatment of the
underlying diseases
Vaccination against am. protein in mice
diminished senile plaque formation and
improved memory.
Nature Medicine, 2001,

7, 18th Jan.

A based experimental therapies based

on degrading enzymes.
Zlokovic et al.:
Neurovascular Pathways and Alzheimer Amyloid peptide. Brain Pathol. , 2005, 15, 78-83

Fibrinoid & Hyalin

disorders of protein metabolism

Fibrinoid Change of
Collagen
vessels and connective tissue damage
plasmorrhagia (leakage of plasma)
deposits of Ag-AB complexes
staining characteristics fibrin - like

Hyaline change
Definition (historical, descriptive):
intra- or extracellular change
of homogenous rose glassy
appearance
in the H&E stained histological
sections

Hyaline change
Extracellular:
corpus albicans, scars, hyalinoses of
serous membranes

Intracellular:
Crooke cells, Mallory hyaline,
Russell bodies

Ultrastructure
Fibrinoid - collagen fibres
surrounded by plasma
proteins may be reversible
Hyalin collagen fibres
increased in thickness,
changed architecture
rather

stable

Hyaline change
Extracellular:
corpus albicans, scars, hyalinoses of
serous membranes

Intracellular:
Crooke cells, Mallory hyaline,
Russell bodies

Significance of Fibrinoid
Change
diminished quality of the collagen

firmness,

permeability)

tendency to thrombosis in the

vessels, aneurysms formation

Significance of Hyalin
Change
diminished quality of the
collagen ( elasticity)
ischemia in organs with
thickened arterial walls
intracellular function, death