Amyloidosis

Prof Dr Sergülen Dervişoğlu
Amyloidosis
Calcification and
stones
Amyloidosis
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Pathologic proteinaceous substance
Deposited between cells
Wide variety of clinical settings
Insidious deposition
Immunological mechanism is probably
responsible
Amyloidosis
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Standart tissue stains
Amorphous
Eosinophilic
Hyaline extracellular substance
Progressive accumulation
Pressure on adjacent cell---atrophy
Amyloidosis
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Differentiate from other hyaline pink
deposits
Collagen, fibrin
Methyl violet--- metachromatic staining
reaction---deep purple
Congo red --- orange red
Polarized microscopy--- green
birefringance
Amyloidosis
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Not chemically distinct
Several different pathogenetic mechanism
Not be considered as a single disease
Three major and several minor biochemical
forms
Physical nature
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Non branching fibril proteins
95%
P component
Glycoprotein
Nonproteineous substances derived from
connective tissue in which amyloid
deposited
Chemical nature
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Amyloid proteins
AL--- amyloid light chain---derived from plasma
cells
AA---amyloid associated---nonimmunoglobulin
protein synthesized by liver
Distinct clinicopathologic settings
Abeta---amyloid found in cerebral lesions of
Alzheimer patients
Amyloidosis
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AL type--- immunoglobulin secreting cells
Monoclonal B cell proliferation
AA type--- secondary amyloidosis
Transthyretin (TTR) mutant form--familial amyloid polyneuropathies
Beta 2 microglobulin---longterm
hemodialysis
Beta amyloid protein---Alzheimer disease
Amyloid clasification
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Based on its constituent chemical fibrils
AA, AL, ATTR
It can be both systemic or localized
Clinically---Primary—Immunocyte
dyscrasias---Monoclonal gammopathy
Secondary---AA---reactive systemic
amyloidosis---underlying chronic disease
Systemic generalized primary
amyloidosis
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Immunocyte dyscrasias
Systemic
AL type
Plasma cell dyscrasias
Multiple myeloma
Monoclonal gammopathy
Abnormal protein
Systemic generalized secondary
amyloidosis
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Underlyig chronic disease---AA type
Reactive
Tbc, Ulcerative colitis,Chr. OM
Bronchiectasis
RA, AS, İnflammatory bowel disease
Hodgkin disease
Renal cell carcinoma
Hereditary familial systemic
amyloidosis
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Familial, rare
Geographic limitation
FMF---AA proteins
Reccurent bouts of inflammation
Familial amyloiditic polyneuropathy
Mutant transthyretin
Localized amyloidosis
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Single organ, tissue
Nodular masses
Tumor forming amyloid accumulation
Lung, larynx, skin, urinary bladder,
tongue, eye
AL type
Peripheral plasmacytes
Endocrine amyloid
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Microscopic deposits of localized amyloid
Endocrine tumors
Medullary carcinoma of thyroid
Islet cell tumor of pancreas
Pheochromocytoma
Unique proteins
Polypeptide hormones
Hemodialysis associated
amyloidosis
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Longterm hemodialysis for renal failure
Deposition of beta2 microglobuline
Can not be filtered through dialysis
membranes
Amyloid deposition in the synovium,joints,
tendon sheath
60-80% of patients
Senile amyloidosis---Amyloid of
aging
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Elderly patients ( 70-80)
Dominant involvement in the heart
Dysfunction
Senile cardiac amyloidosis
Restrictive cardiomyopathy
Arrhythmias
Normal or mutant form of transthyretin
Systemic—lungs, pancreas, spleen
Pathogenesis
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Stimulus----soluble precursor---Insoluble fibers
Unknown ( Carcinogen?)---Monoclonal B cell
proliferation---plasma cells---Ig Light chain--limited proteolysis---P component---AL amyloid
Chronic inflammation---Macrophage activation--IL1,6 secretion---Liver cells---SAA---Limited
proteolysis---P component--- AA amyloid
Genetically determined alteration---abnormal
TTR---ATTR amyloid
Organ findings in amyloidosis
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No distinct or consistent pattern of
distribution
Secondary form tend to be severe
systemic involvement---kidneys, liver,
spleen, lymph nodes, adrenal glands,
thyroid
Immunocyte associated--heart,kidney,gastrointestinal tract,
peripheral nerves,skin, tongue
Macroscopic apperarance
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Enlarged, firm
Waxy appearance
Sufficiently large deposit---iodine
painting of cut surface---yellow color
turns to blue violet—after application of
sulfuric acid
Microscopy
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Staining with specific dyes
Congo red
Cresyl violet
Electron microscopic confirmation
Polarized microscopy
Specific immunohistochemistry for
subtypes AA, AL, ATTR
Kidney amyloidosis
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Most common
Most serious
Renal amyloidosis is the major cause of
death
Normal in size and color or enlarged
In advanced case shrunken/contracted--vascular narrowing---due to deposition
of amyloid in arteriolar wall
Kidney amyloidosis microscopy
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Glomerular accumulation/ Mesangial matrix
Interstitial peritubular tissue
Arteries, arterioles
Widening of glomreular capillaries basal
membrane
Distortion of vascular tuft
Glomeruli turn into confluent masses of
amyloid
Amyloidosis of the spleen
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Splenomegaly moderate to marked
Two patterns of deposition
Deposition limited to splenic follicles—
white pulp---tapioca like granules--SAGO spleen
Amyloid depoistion in sinusoidal walls and
connective tissue framework---red pulp--maplike---LARDECEOUS spleen
Amyloidosis of liver
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Moderate to marked hepatomegaly
Amyloid deposition in Disse space
Progressive pressure atrophy of adjacent
hepatocyte
Total replacement of liver parenchyma
Vascular involvement, Kupffer cell
deposition
Normal liver function is usually preserved
Amyloidosis of heart
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Enlarged, firm
No significant macroscopic change
Focal subendocardial accumulation
Between muscle fibers
Conduction system may be damaged
Pressure atrophy of fibers
Intractable heart failure
Amyloidosis of other organs
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Adrenals, pitutary glands, thyroid
Adrenals first site is zona glomerulosa
Replacement of parenchyma
GIS---early lesions blood vessel walls—Bx
diag
Nodular deposition in the tongue
Respiratory tract
Alzheimer---brain
Clinical correlation
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No clinical findings
It may cause death
Magnitude of deposits
Particular organ or sites affected
Nonspesific general symptoms
Weight loss, weakness,syncope
Clinical findings of amyloidosis
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Renal involvement---proteinuria
Nephrotic syndrome
Renal failure---uremia
Cardiac amyloidosis---insidious congestive
heart failure
Conduction disturbances
Gastrointestinal amyloidosis--asymptomatic---malabsorption, diarrhea
Prognosis
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Generalized amyloidosis poor prognosis
Immunocyte derived form---2 years
median survival
Myeloma associate ones---poorer
prognosis
Depends on the control of underlying
cause
Pathologic calcification
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Abnormal deposition of calcium salts
Together with small amounts of other
mineral salts
Ca phosphate
Ca carbonate
Other salts
Calcification
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Dystrophic calcification
Nonviable/dying tissue
Metastatic calcification
Vital tissues
Dystrophic calcification
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Areas of necrosis
Coagulative, liquefactive type
Enzymatic fat necrosis
Whenever the necrotic tissue persist for
long period of time
Dystrophic calcification
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Not dependent on an increase in the
calcium content of the blood
Influenced by local relative alkalinity of
the damaged tissue
Abnormal amount of phosphate
accumulating in necrotic tissue may favor
the deposition of Ca salts
Dystrophic calcification
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Atheroma plaques in advanced
atherosclerosis
Aging or damaged heart valves
Calcific aortic stenosis
Dead fetus intrauterin
Lithopedion
Macroscopy
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Fine, white granules
Clumps
Gritty deposits
Stone like appearance in lymph nodes (
Tbc)
In fat necrosis---Ca and released fatty
acids---SOAPS
Microscopy
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Hematoxylen/eosin stains---basophilic,
amorphous, granular, clumped
Intracellular
Extracellular
Both location
In the course of time---heterotopic bone
formation in the focus of calcification
Single necrotic cell
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Progressive acquesition of outer layers by
mineral deposits
Lamellated configuration
Psammoma bodies
Resemblance to grains od sand--Psammom=sand---Greek word
Psammoma bodies
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Papillary carcinoma of thyroid
Papillary carcinoma of ovary
Meningioma
In asbestosis---calcium iron salts---long
slender spicules---exotic dumbbell forms
Pathogenesis
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Formation of crystalline calcium phosphate
mineral---apatite form ( resembling
hydroxyapatite of bone)
Initiation
Propagation
Intracellular calcification---in the mitochondria
of dead or dying cell
Extracellular calcification---phospholipids in
membrane bound vesicles
Metastatic calcification
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Calcification in previously undamaged
tissue
Interstitial tissue of blood vessels
Kidneys
Lungs
Gastric mucosa
Morphology is similar with dystrophic
calcification
Hypercalcemia
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Hyperparathyroidism
Vit D intoxication
Systemic sarcoidosis
Milk-alkali syndrome
Hyperthyroidism
Idiopathic hypercalcemia of infancy
Addison’s disaese
Increased bone catabolism
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No clinical dysfunction
Massive involvement of lungs---X-ray
changes-respiratory difficulties
In the kidney---nephrocalcinosis---in
time---renal damage
Increased bone catabolism
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Disseminated bone tumors
Multiple myeloma
Metastatic cancer leukemia
Pathologic ossification
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Preceeded by calcification
Transformed fibroblasts---osteoblasts
Heterotopic bone formation
Bone marrow
Reactive, metaplastic
Myozitis ossificans---localized after
trauma to a muscle
Stones or calculi
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In urinary tract---by precipitation of chemical
salts in urine
Infection
Stasis
Increased urinary concentration of crystalloids
Changes of a physical and chemical nature of
urine or urinary tract that favor the
precipitation
Types of urinary tract stones
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White stones---mixtures of uric acid, Ca
oxalate and phosphates
Certain constituents predominate
Uric acid and cystine---precipitate in an
acid urine
Phosphate---associated with alkaline
urines
Oxalate stones---any pH
Renal calculi
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Obstruction of outflow of urine
Stasis---Promote infection
Pyelonephritis
Renal colic pain
Dilatation of ureter or renal pelvis
Hydroneprosis
Gall stones
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Normal constituents of bile
Cholesterol
Calcium biluribinate
Calcium carbonate
Main substances
Pure gallstones
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Excess of the stone forming substance in
bile
Disturbance of liver function or
metabolism
Cholesterol stone mostly
Pigment stones ( Ca biluribinate)
Mixed gallstones
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Most common form ( 80%)
Exact mechanism of their formation is
uncertain
Multiple
Huge numbers
Combined gall stones
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Solitary stone
Cholesterol nucleus
Outer shell similar to a mixed gallstone
References and further reading
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Robbins Pathologic Basis of Disease, Cotran, Kumar 2004
Pathology Illustrated, Macfarlane, Reid,Callande 2000
Sandritters Color Atlas and Textbook of Macropathology,
Thomas, Kirstn, 1984
Basic Pathology, 6th ed, Kumar, Kotran, Robbins
Pathology Rubin, Farber, 1999
Mohan Harsh Textbook of Pathology, 2005
Cerrahpaşa Pathology archieves
Internet (various medical web sites)