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Extracellular Pathology

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Title: Extracellular Pathology


1
Extracellular Pathology
  • Amyloidosis
  • Pathological calcification
  • Ageing

2
Amyloid and Amyloidosis
  • A Set of Disorders The main feature is the
    extracellular deposition of proteins arranged in
    the form of a Beta-pleated sheet
  • Amylum Latin for starch
  • Term first used By Virchow in 1854
  • Protein.Friedreich and Kekule. 5 years later

3
Amyloidosis
  • Amyloidosis is a clinical disorder caused by
    extracellular deposition of insoluble abnormal
    fibrils that injure tissue.
  • The fibrils are formed by the aggregation of
    misfolded, normally soluble proteins.
  • In humans, about 23 different unrelated proteins
    are known to form amyloid fibrils.

4
Amyloidosis
  • All types of amyloid consist of a major fibrillar
    protein that defines the type of amyloid
    (approximately 90) plus various minor
    components.
  • Although each type of fibril may be associated
    with a distinct clinical picture, all share
    certain physical and pathologic properties

5
  • Organs affected by amyloid
  • Larger, Paler, Firmer
  • How do we identify Amyloid in tissues?
  • Macroscopically (Grossly)
  • Waxy, Sharper cut edges, Lugols iodine (black).
  • Microscopically
  • Light Microscopy-
  • Amyloid is eosinophilic and stains with Congo Red
  • Polarized light Apple Green Birefringence.
  • Electron Microscopy Rigid non branching fibrils
    (7.5 nm to 10 nm in diameter)

6
Kidney
7
Heart, Lugols iodine
8
HE Stain
9
Congo Red Stain.
10
Apple Green Birefringence
11
Electron Microscope
12
  • The Beta- Pleated sheet is the unifying feature
    of the amyloidoses
  • Basis of 1) Congo Red reaction
  • 2) Fibrillar ultrastructure
  • 3) Resistance to proteolytic
  • digestion

13
Why?
  • Protein Misfolding
  • Intrinsic tendency to misfold (Transthyretin)
  • Misfolding and aggregation at high concentration
    (Beta Microglobulin)
  • Point mutations (Hereditary amyloidosis)
  • Review Molecular mechanisms of amyloidosis.
    Merlini G, Bellotti V. NEJM August 2003
    349583-96

14
Classification
  • Older classifications 1 and 2
  • More useful to classify on the basis of
  • 1) Nature of protein involved
  • 2) Anatomical distribution
  • 3) Inherited or acquired

15
Acquired Systemic Amyloidosis
  • 1) Amyloidosis of immune origin. AL type
  • Acquired, Systemic form
  • Protein precursor is usually immunoglobulin light
    chain.
  • Occurs in association with a monoclonal (i.e.
    neoplastic) proliferation of B lymphocytes or
    plasma cells e.g.
  • Myeloma (Lambda chains)
  • Waldenstroms macroglobulinaemia (LPL)

16
  • AL amyloid proteins Intact immunoglobulin light
    chain or the amino terminal fragment of a chain
    or both. (mostly lambda chains)
  • 90 of these patients have Bence Jones proteins
  • Amyloid accumulation Two step process
  • 1) Secretion of excess amounts of monoclonal
    light chain
  • 2) Conversion to Beta pleated form.

17
Clinical features
  • Middle to old age
  • MgtF
  • 90 have a Bence Jones protein
  • Bone marrow excess plasma cells
  • Manifestations
  • Neuropathy, Restrictive Cardiomyopathy, Skin
    manifestations, Polyarthropathy, Macroglossia,
    Carpal Tunnel Syndrome
  • (Heart, CNS, Joints, Skin, Tongue, Soft Tissues)

18
Immunofluorescence microscopy with antibody to
the lambda light chain.
19
Cardiac
2nd Year Pathology 2009
20
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21
Acquired Systemic Amyloidosis
  • 2) Haemodialysis associated Amyloid
  • Acquired, systemic
  • Protein is Beta-2-microglobulin.
  • Normally broken down by kidneys
  • A naturally occurring amyloidogenic protein not
    filtered by dialysis membranes
  • After 7 years on dialysis 30 of patients get
    Carpal Tunnel Syndrome (after 10 years 50)
  • Joints, synovium, tendon sheaths

22
Acquired Systemic Amyloidosis
  • 3) Reactive Systemic Amyloidosis
  • Also known as secondary amyloid or AA type
    amyloid
  • Acquired, systemic form
  • Protein precursor is serum amyloid A (SAA)
  • Acute phase reactant which markedly increases
    with tissue injury or inflammation under the
    influence of IL1, TNF and IL-6
  • AA is a cleavage product of SAA.
  • Distribution of amyloid kidney, liver, spleen,
    adrenals, thyroid many other tissues.
  • Diagnosis Rectal Biopsy

23
Disease Associations
  • 1) Chronic infection T.B., Leprosy, Syphilis,
    Chronic osteomyelitis, Bronchiectasis
  • 2) Chronic inflammation
  • Reiters disease, Whipples disease
  • 3) Chronic autoimmune disease
  • R.A., I.B.D., Connective Tissue Disease
  • 4) Long standing paraplegia. (UTI)
  • 5) Neoplasms
  • Renal adenocarcinoma and Hodgkins disease

24
Liver
25
Adrenal
26
Hereditary Systemic Amyloidosis
  • Rare.
  • Most common Familial Mediterranean Fever.
  • Less common Three types
  • Neuropathic.
  • Cardiopathic.
  • 3) Nephropathic.
  • The Amyloid protein is usually Transthyretin
    (Prealbumin). Transthyretin is also associated
    with a form of Amyloid known as Systemic Senile
    Amyloid, where amyloid is systemically deposited,
    mainly in the heart in elderly individuals.

27
  • Familial Mediterranean Fever
  • Commonest form of hereditary systemic amyloidosis
  • Autosomal Recessive, Gene on Chromosome 16
  • AA type amyloid
  • Two manifestations of the disease
  • Short febrile attacks with pain mimicking
    pleurisy, peritonitis or
  • synovitis
  • Amyloidosis Manifest early in life
  • Death before 40 without Renal Transplant
  • Treated with Colchicine (Stabilization of
    inflammatory cells)

28
Localized amyloidosis
  • Endocrine associated
  • Pituitary - age related
  • Islets of Langerhans - NIDDM related
  • Medullary Carcinoma of Thyroid (Calcitonin)
  • Intacerebral
  • Alzheimers, Spongiform Encephalopathy

29
Islets
30
Amyloid angiopathy
2nd Year Pathology 2009
31
Alzheimers disease
32
Medullary Thyroid Carcinoma
33
Pathological Calcification
  • Dystrophic Calcification
  • Metastatic Calcification
  • Idiopathic Calcification

34
Dystrophic Calcification
  • Normal serum calcium/phosphate
  • Nonviable or dying tissues
  • Occurs in atherosclerosis, damaged valves,
    necrosis (coagulative, caseous, liquefactive),
    Leiomyomas
  • Monckebergs medial sclerosis
  • Intracellular / Extracellular
  • Two phases Initiation and Propagation

35
Dystrophic Calcification
Tricuspid valve
Stomach
36
Metastatic Calcification
  • Must be associated with elevated Calcium.
  • Occurs in vital tissues
  • Aetiology
  • Increased PTH
  • Hyperparathyroidism
  • Bone destruction
  • Tumour (MM, Leukaemia), Skeletal Mets (Breast
    Ca.)
  • Increased bone turnover (Pagets),
    Immobilisation.
  • Vitamin D related disorders
  • Excess Vitamin D
  • Sarcoidosis
  • Renal Failure
  • Retention of Phosphate, (secondary HyperPTH)

37
Metastatic Calcification
  • Kidney Around tubules - Renal Failure.
  • Lung Alveolar walls.
  • Stomach Fundal glands.
  • Identification of Calcium
  • Von Kossa

2nd Year Pathology 2009
38

39
Hyperparathyroidism
  • Primary, Secondary, Tertiary
  • 1 Increased bone re-absorbtion and
    mobilization of calcium from bone
  • Increased renal tubule re-absorption.
  • Increased Vit. D activity
  • Bones, stones , (psychic moans) and abdominal
    groans

2nd Year Pathology 2009
40
  • Aetiology
  • 1) Parathyroid adenoma. 75
  • 2) Hyperplasia. 10-15
  • 3) Parathyroid carcinoma lt5
  • (MEN 1 or MEN2a)
  • Secondary Renal Failure, Osteomalacia.

41
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42
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43
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44
Ageing
  • Aging is NOT a disease
  • The changes that occur with aging make aged
    persons more susceptible to disease
  • Aging is probably multifactorial involving both
    internal (Genetically programmed) and external
    (Tissue damage) factors that combine to exert
    their effects

45
  • Theories of Aging
  • Cellular Changes.
  • There is cumulative free radical damage to DNA
    and to proteins (perhaps due to lack of
    antioxidants).
  • Genetics
  • Another theory suggests that aging is determined
    by genetic programming and malfunction.
  • 1962 The Hayflick phenomenon. Telomeres and
    Telomerase
  • Progeria (Werners syndrome). DNA Helicase
  • Loss of Homeostasis
  • Environmental Stress
  • Neuroendocrine Dysfunction
  • Nutrition

46
Organ Systems
  • Central Nervous System
  • Stroke.
  • Alzheimers.
  • Neuronal loss.
  • Eye
  • Cataracts.
  • Presbyopia.
  • Ear
  • Presbycusis.

2nd Year Pathology 2009
47
  • Cardiovascular System
  • Atheroma
  • Calcification (Senile calcific aortic sclerosis)
  • Senile Amyloid.
  • Urinary Tract
  • Decreased GFR.
  • Increased UTI in women.
  • Musculoskeletal System
  • Decreased bone mass.
  • Osteoarthritis.

48
  • Genital Tract
  • Menopause leads to atrophy of ovaries, uterus,
    and breasts. The epithelium of the vagina and
    vulva also become thinner.
  • Prostatic Hyperplasia.
  • Skin
  • Decreased elasticity.
  • Senile lentigines

2nd Year Pathology 2009
49
Telomere
50
Timing of Aging Telomeres
  • Telomerase stabilizes telomere lengths
  • Active in germ cells, absent in most somatic
    cells
  • May be reactivated in cancer cells
  • When cells replicate, small portion of telomere
    not duplicated
  • Telomere shortening growth checkpoint signal
    for cell to become senescent
  • Mechanism for cells to count their divisions

51
Genetic Damage and Aging Werners Syndrome
DNA helicases are known to be involved in the
repair, replication and expression of the genetic
material. Defects in DNA helicase lead to
premature aging Rapid accumulation of genetic
damage, mimicking the aging process Premature
aging also seen in Cockayne syndrome and ataxia
telangiectasia, other inherited defects in DNA
repair.
52
Summary
  • Ageing
  • Effects a combination of
  • Intrinsic factors telomere lengths
  • Extrinsic factors progressive DNA (and other
    cellular) damage
  • The latter may be accelerated by inherited
    defects in DNA repair.

53
Summary
  • Amyloid.
  • Appearance / identification
  • Types of acquired and inherited amyloidosis
  • Pathological calcification.
  • Dystrophic / Metastatic / Idiopathic
  • Causes and Consequences
  • Ageing
  • Theories of Aging
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