- Amyloidosis is characterized by the abnormal deposition of amyloid protein in tissues and organs. The amyloid protein forms non-branching fibrils that take on an abnormal beta-pleated sheet configuration.
- There are multiple subtypes of amyloidosis based on the type of amyloid protein deposited, including AL amyloidosis associated with plasma cell dyscrasias and AA amyloidosis associated with chronic inflammatory conditions.
- Amyloidosis can be systemic, involving multiple organ systems, or localized to a single organ. Common sites of involvement include the kidneys, liver, spleen, heart, and skin. Deposition of amyloid protein in organs can lead to organ dysfunction and failure.
Difference between reversible and irreversible cell injury,Mechanism of cell ...Rukhshanda Ramzaan
Cell Injury: Any change resulting in loss of the ability to maintain the normal or adapted homeostatic state.
Agents that cause cell injury
• Hypoxia / Ischemia (loss of blood supply)
• Microbial
• Parasitic
• Chemical
• Physical
• Trauma
• Genetic
• Nutritious
• Environmental
Types of Cell injury
Reversible Cell Injury
Pathologic changes that can be reversed in mild cellular injury when the stimulus is removed. Cell injury is reversible only up to a certain point otherwise it will be irreversible.
Changes in reversible cell injury
Cellular Swelling: Due to accumulation of intracellular water and endoplasmic reticulum & mitochondria.
Clumping of chromatin.
Irreversible Cell injury
Pathologic changes that are permanent and cause cell death, they cannot be reversed to normal state.
Changes in irreversible cell injury
Irreversible injury is marked by severe mitochondrial vacuolization, extensive damage to plasma membranes, detachment of ribosomes from the granular endoplasmic reticulum (ER). Injury to lysosomal bodies leads to leakage of lysosomal enzymes into the cytoplasm and condensation, fragmentation and lysis of nuclei.
Amyloidosis is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damange and functional compromise. (Robbins Basic Pathology, 9th Edition)
The following slideshow deals with the classification of Amyloidosis:
A Powerpoint presentation on the epidemiology, etiology, pathogenesis, clinical features, diagnostic work up and treatment of the common types of amyloid.
Difference between reversible and irreversible cell injury,Mechanism of cell ...Rukhshanda Ramzaan
Cell Injury: Any change resulting in loss of the ability to maintain the normal or adapted homeostatic state.
Agents that cause cell injury
• Hypoxia / Ischemia (loss of blood supply)
• Microbial
• Parasitic
• Chemical
• Physical
• Trauma
• Genetic
• Nutritious
• Environmental
Types of Cell injury
Reversible Cell Injury
Pathologic changes that can be reversed in mild cellular injury when the stimulus is removed. Cell injury is reversible only up to a certain point otherwise it will be irreversible.
Changes in reversible cell injury
Cellular Swelling: Due to accumulation of intracellular water and endoplasmic reticulum & mitochondria.
Clumping of chromatin.
Irreversible Cell injury
Pathologic changes that are permanent and cause cell death, they cannot be reversed to normal state.
Changes in irreversible cell injury
Irreversible injury is marked by severe mitochondrial vacuolization, extensive damage to plasma membranes, detachment of ribosomes from the granular endoplasmic reticulum (ER). Injury to lysosomal bodies leads to leakage of lysosomal enzymes into the cytoplasm and condensation, fragmentation and lysis of nuclei.
Amyloidosis is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damange and functional compromise. (Robbins Basic Pathology, 9th Edition)
The following slideshow deals with the classification of Amyloidosis:
A Powerpoint presentation on the epidemiology, etiology, pathogenesis, clinical features, diagnostic work up and treatment of the common types of amyloid.
by post graduates from Maratha Mandal's NathajiRao Halgekar Institute of Dental Sciences, Belgavi.
A step wise presentation of Amylodosis covering,
INTRODUCTION
DEFINITION
HISTORY
PHYSICAL NATURE
CHEMICAL NATURE
CLASSIFICATION
PATHOGENESIS
STAINING CHARACTERISTICS
DIAGNOSTIC TESTS
MORPHOLOGY
CLINICAL FEATURES
TREATMENT
PROGNOSIS
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
2. Gist - AMYLOID
• It’s only a manifestation of different diseases
• it’s an abnormal protein
• It’s deposited Extracellularly
• It’s bland and Non-reactive
• Enzyme resistant
• Affects all tissues
• It causes organ failure by pressure atrophy
APR-2015-CSBRP
3. Gist - AMYLOID
Two processes are associated with
such deposition
• Prolonged inflammation
• Excessive immunoglobulin synthesis
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4. Amyloid
Amyloid is a pathologic proteinaceous
substance, deposited between cells in
various tissues and organs of the body in
a wide variety of clinical settings.
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5. AmyloidAmyloid
With the light microscope and standard
tissue stains, amyloid appears as
• An amorphous, eosinophilic, hyaline
like, extracellular substance
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6. DD Hyaline & Amyloid
FeatureFeature HyalineHyaline AmyloidAmyloid
Location Both extra & intracellular Extracellular
Nature Protein / others Protein
Inflammation Inflammatory reaction No inflammation
Etiology Variety of agents Immunological
H&E Eosinophilic Eosinophilic
Congo red Negative Positive
CR+Polarizer No change Apple green
EM variety of morphology Nonbranching fibrils
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7. Amyloid
• Is not a single protein
• Chemically different proteins with
identical staining properties
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8. Amyloid – Physical nature
By electron microscopy:By electron microscopy:
(It’s common to all amyloid proteins(It’s common to all amyloid proteins))
• Non-branching fibrils
• Diameter of 7.5-10 nm
• cross-β-pleated sheet conformation
This β-pleated nature is responsible for its
special staining character
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10. The Nature of Amyloid
Ultrastructure
Structure of an amyloid fibril
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11. Amyloid – Chemical nature
Mainly composed of:
1. Fibrillary protein - 95%
2. P-component - 5%
3. Glycoprotein - a fraction
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12. gist - The Nature of Amyloid
• Physical Nature:
• Electron microscopy: Amyloid material contains two
components. (1) Rigid nonbranching fibrils* (7.5 to 10 nm):
Constitute the major component (about 90%) (2) Pentagonal
rod shaped sub-unit (P components): Forms 10% of amyloid
tissue and is a glycoprotein (variable PAS positive staining).
• X-ray diffraction analysis: Characteristic β-pleated
configuration* in both major subtypes of amyloid.
• Chemical nature:
• Peptide mapping analysis of the sequence of amino
acids: Of the 15 biochemically distinct forms
identified, 3 are major chemical types of amyloid: (1) Amyloid
of light chain origin (AL) from plasma cells, (2) Unique
nonimmunoglobulin protein synthesized in the liver (AA), (3)
Aβ amyloid in cerebral lesion of Alzheimer disease
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13. Classification
Amyloid may be:Amyloid may be:
Systemic (generalized), involving several
organ systems, or
Localized, when deposits are limited to a
single organ, such as the Heart, Skin et.c.
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14. Localized Amyloid Deposits
Endocrine associated:
• Amyloid deposits in the stroma of medullary thyroid carcinoma, a C-
cell tumor; amyloid is derived from a polypeptide hormone calcitonin.
• Amyloid deposits in the stroma of islet cell tumors, particularly those
producing insulin (amyloid is produced by proteolysis of insulin or its
prohormone).
Senile amyloidosis:
• Deposits are common in the aged (seventies and eighties); found in
heart (atria affected more frequently than ventricles) and brain (as
senile plaques).
• The plaques found in Alzheimers disease is derived from β-amyloid
protein (Aβ), derived from a glycoprotein called amyloid precursor
protein (APP).
Other localized deposits: Microscopic deposits to nodular
masses in sites such as lung, larynx, skin, bladder, and tongue.
Consist of AL protein in most cases.
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15. Clinicopathologic Category
Associated Diseases
Major Fibril
Protein
Chemically Related
Precursor Protein
Systemic (Generalized) Amyloidosis
Immunocyte dyscrasias with
amyloidosis (primary amyloidosis)
Multiple myeloma and other
monoclonal B-cell proliferations
AL
Immunoglobulin light
chains, chiefly λ type
Reactive systemic amyloidosis
(secondary amyloidosis)
Chronic inflammatory conditions AA SAA
Hemodialysis-associated
amyloidosis
Chronic renal failure Aβ2
m β2
-microglobulin
Hereditary amyloidosis
Familial Mediterranean fever — AA SAA
Familial amyloidotic neuropathies
(several types)
— ATTR Transthyretin
Systemic senile amyloidosis — ATTR Transthyretin
Localized Amyloidosis
Senile cerebral Alzheimer disease Aβ APP
Endocrine
Medullary carcinoma of thyroid — A Cal Calcitonin
Islet of Langerhans Type II diabetes AIAPP Islet amyloid peptide
Isolated atrial amyloidosis — AANF Atrial natriuretic factor
Prion diseases
Various prion diseases of the
CNS
Misfolded prion
protein (PrPSC
)
Normal prion protein
PrP
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16. Classification of Systemic AmyloidosisClassification of Systemic Amyloidosis
on clinical groundson clinical grounds
• Primary amyloidosis, when associated with
some immunocyte dyscrasia, or
• Secondary amyloidosis, when it occurs as a
complication of an underlying chronic
inflammatory or tissue destructive process.
• Hereditary or familial amyloidosis constitutes a
separate, albeit heterogeneous group, with
several distinctive patterns of organ
involvement.
• Hemodialysis associated Amyloidosis
• Localized amyloidosis - (A). Endocrine
associated, (B). Senile, and (C). Others
APR-2015-CSBRP
17. Immunocyte Dyscrasias with
Amyloidosis (Primary Amyloidosis)
• Most common form of amyloidosis
• many of these patients have some form of
plasma cell dyscrasia / B-cell dyscrasia
• Amyloid has AL composition
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18. Reactive Systemic Amyloidosis
• Secondary to an inflammatory condition
• Protracted breakdown of cells
• Composed of AA protein
Chronic osteomyelitis Rheumatoid arthritis
Bronchiectasis Connective tissue disease
Tuberculosis RCC
Leprosy Hodgkin’s disease
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19. Patients on long-term hemodialysis for renal failure
High β2-microglobulin in the serum
Amyloid deposits in the synovium, joints, and
tendon sheaths
Hemodialysis-Associated
Amyloidosis
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20. • Many familial forms of amyloidosis
• Confined to limited geographic areas
• The most common is familial Mediterranean fever
• Others - familial amyloidotic polyneuropathies
Heredofamilial Amyloidosis
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21. Microscopic localized deposits of amyloid in
endocrine tumors,
Eg: Medullary carcinoma of the thyroid gland,
Islet tumors of the pancreas
Pheochromocytomas and
Undifferentiated carcinomas of the stomach
Amyloid derived from hormones or unique proteins
Endocrine Amyloid
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22. Several well-documented forms of amyloid
deposition occur with aging
Senile systemic amyloidosis - systemic
deposition of amyloid in elderly patients
called senile cardiac amyloidosis
Amyloid of Aging
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23. Amyloid – Chemical nature
Fibrillary component: 15 bio-chemically distinct
forms have been identified
Three are most common:
(1) AL (amyloid light chain) immunoglobulin light
chains
(2) AA (amyloid-associated) nonimmunoglobulin
protein synthesized by the liver and
(3) Aβ amyloid is found in Alzheimer disease
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24. Proposed Scheme of Pathogenesis of Two
Major Forms of Amyloid Fibrils
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25. Pathogenesis of Amyloidosis
• Amyloid fibrils (AL protein or AA protein) formed in
vivo from a variety of polypeptide fragments, derived
either from immunoglobulin of plasma cell origin or
from other protein (SAA) of hepatocytic origin.
• Amyloidogenic proteins (Immunoglobulin light
chains or SAA) present in the blood is deposited in
various sites following limited proteolysis by the
action of monocyte-derived enzymes.
• Thus, mononuclear phagocyte system may play a
role by taking up immunoglobulins, Ag-Ab
complexes, or other proteins and produce necessary
polypeptides for formation of amyloid fibrils.
APR-2015-CSBRP
34. Bilateral periorbital
ecchymosis (raccoon eyes)
and mild proptosis.
Another example of "raccoon
eyes" which is a clinical sign of a
base of skull fracture.
APR-2015-CSBRP
36. Kidney in Amyloidosis
Gross: The organ is usually
enlarged and pale but a small
scarred kidney results in long
standing cases due to
secondary ischemic changes.
Micro: Amyloid is deposited
primarily in the glomeruli.
Mesengial deposition and the
deposits along basement
membrane cause capillary
narrowing and distortion of
glomerular tuft. The arterioles,
and interstitial tissue between
the tubules are also affected.
APR-2015-CSBRP
37. Kidney in Amyloidosis
Clinical impact:
Renal involvement in
amyloidosis is most
common and result is
nephrotic syndrome,
often as the
presenting feature. It
is the most serious
manifestation and
major cause of death.
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38. Renal biopsy in AL amyloidosis
Staining with anti-K light chain Abs
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39. Renal biopsy in secondary AA amyloidosis
Glomerulus is strongly positive for AA protein
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40. Liver in Amyloidosis
Gross: Liver is enlarged,
heavy, pale, and firm.
Micro: Amyloid is deposited in
the space of Disse between the
endothelium and the liver cells,
and progressively encroaches
on adjacent hepatocytes and
sinusoids. The liver cells
undergo atrophy. Vascular
involvement and Kupffer cell
depositions are frequent.
Clinical impact: Liver
function is preserved in the
presence of marked
involvement.
APR-2015-CSBRP
43. Spleen in Amyloidosis
Gross: Spleen is enlarged and firm. Focal distribution is common.
The cut surface shows numerous translucent nodules distributed
throughout the red pulp (characteristic appearance, called ‘sago
spleen’). A diffuse type is also recognized.
Micro: In localized type amyloid is laid down in the walls of the
arterioles in the white pulp and subsequently replaces the malpighian
bodies. In diffuse type, amyloid is laid down in the walls of the
sinuses and tends to spare the follicles. Fusion of early deposits lead
to large map-like areas of amyloidosis (lardaceous spleen).APR-2015-CSBRP
48. Lardaceous spleen
• fat from the abdomen of a pig, especially as
prepared for use in cooking
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49. Lardaceous spleen
• fat from the
abdomen of a
pig, especially
as prepared for
use in cooking
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50. Heart in Amyloidosis
Cardiac involvement is the major
manifestation of primary
amyloidosis. It occurs in multiple
myeloma and usually in elderly
people.
Gross: Heart is enlarged, rigid, and
firm.
Micro: Begin with focal
subendocardial deposition. In due
course widespread deposition of
amyloid in the walls of blood
vessels and in the interstitial tissue
surrounding and replacing muscle
fibers.
Clinical impact: Cardiomegaly with intractable heart failure. Heart block
and arrhythmia due to involvement of conduction system are common.
Condition mimicking constrictive pericarditis due to rigidity of the muscle.
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54. Immunocyte-derived Systemic
Amyloidosis
• Found in with 5 to 15% multiple myeloma patients and in patients with
B-cell dyscrasias (monoclonal B-cell proliferations).
• Amyloid is systemic indistribution (AL type) and derived from Ig light
chains (chiefly λ type).
• An excess of corresponding light chain is usually present in the blood
and secreted in urine as Bence-Jones protein
Organ involvement and its effect:
• Kidney involvement is a major feature and usual cause of death.
• Myocardium : refractory heart failure.
• Tongue: enlargement interferes with speech.
• Esophagus: dysphagia.
• Intestine: lesions lead to obstruction, bleeding, and perforation.
• Skin: deposits cause purpura.
• Nerve: peripheral neuropathy.
• The liver, spleen, lungs, and endocrine organs are affected less
frequently.
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56. Diagnosis of Amyloid Disease in Life
• Amyloid may be demonstrated in biopsy material obtained from liver,
spleen, kidney, intestine, and bone marrow. Most common site of
biopsy is kidney, when renal manfestations are present.
• Tissue involved by amyloidosis has a tendency to bleed when
subjected to trauma. Biopsy of gingiva and rectal mucosa has
advantage over other sites in that, and should hemorrhage occur, it
can readily be controlled.
• Fine needle aspiration biopsy of the abdominal fat is also an easily
followed and extemely useful procedure for detection of systemic
amyloidosis.
• Appearance in routine stains: With light microscope and standard
tissue stains, amyloid appears as an amorphous, eosinophilic,
hyaline, extracellular substance.
• Appearance by special stain (Congo red): Amyloid stains an orange
red color under ordinary light but when the stained slide is viewed in a
polarizing microscope, a characteristic green birefringence is
imparted.
• Other investigations: In immunocyte-associated amyloidosis, serum
and urine protein electrophoresis, and immunoelectrophoresis. Bone
marrow aspiration for plasmacytosis.
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63. Demonstration of Amyloid
Stain Result Technique
Lugol’s Iodine Mahagany brown – Blue On Fresh tissue
Methyl violet Pink to Red Metachromasia
Thiflavine-T Bright red fluorescence Fluorescent technique
Thioflavine-S Bright red fluorescence Fluorescent technique
Alcian blue Green Chemical
Silver impregnantion Black Impregnation
Congo red Red Beta-pleated nature
CR + Polarization Apple green birefringens Polarization
Sirius red Green Polarization
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Figure 6-53 Structure of an amyloid fibril, depicting the β-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified from Glenner GG: Amyloid deposit and amyloidosis. The β-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
Figure 6-53 Structure of an amyloid fibril, depicting the β-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified from Glenner GG: Amyloid deposit and amyloidosis. The β-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
*responsible for unique staining and biological properties (e. g., orange red staining under ordinary light and apple green birefringence while examined under polarized light after Congo red staining).
On clinical grounds, the systemic, or generalized, pattern is subclassified into primary amyloidosis, when associated with some immunocyte dyscrasia, or secondary amyloidosis, when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process. Hereditary or familial amyloidosis constitutes a separate, albeit heterogeneous group, with several distinctive patterns of organ involvement.
Immunocyte Dyscrasias with Amyloidosis (Primary Amyloidosis).
Hemodialysis associated Amyloidosis
Localized amyloidosis - (A). Endocrine associated, (B). Senile, and (C). Others
Immunocyte Dyscrasias with Amyloidosis (Primary Amyloidosis).
Amyloid in this category is usually systemic in distribution and is of the AL type. With approximately 1275 to 3200 new cases every year in the United States, this is the most common form of amyloidosis. In many of these cases, the patients have some form of plasma cell dyscrasia. Best defined is the occurrence of systemic amyloidosis in 5% to 15% of patients with multiple myeloma, a plasma-cell tumor characterized by multiple osteolytic lesions throughout the skeletal system ( Chapter 14 ). The malignant B cells characteristically synthesize abnormal amounts of a single specific immunoglobulin (monoclonal gammopathy), producing an M (myeloma) protein spike on serum electrophoresis. In addition to the synthesis of whole immunoglobulin molecules, only the light chains (referred to as Bence Jones protein) of either the λ or the κ variety may be elaborated and found in the serum. By virtue of the small molecular size of the Bence Jones protein, it is frequently excreted in the urine. The amyloid deposits contain the same light chain protein. Almost all the patients with myeloma who develop amyloidosis have Bence Jones proteins in the serum or urine, or both, but a great majority of myeloma patients who have free light chains do not develop amyloidosis. Clearly, therefore, the presence of Bence Jones proteins, although necessary, is by itself not enough to produce amyloidosis. We discuss later the other factors, such as the type of light chain produced (amyloidogenic potential) and the subsequent handling (possibly degradation) that may have a bearing on whether Bence Jones proteins are deposited as amyloid.
The great majority of patients with AL amyloid do not have classic multiple myeloma or any other overt B-cell neoplasm; such cases have been traditionally classified as primary amyloidosis because their clinical features derive from the effects of amyloid deposition without any other associated disease. In virtually all such cases, however, monoclonal immunoglobulins or free light chains, or both, can be found in the serum or urine. Most of these patients also have a modest increase in the number of plasma cells in the bone marrow, which presumably secrete the precursors of AL protein. Clearly, these patients have an underlying B-cell dyscrasia in which production of an abnormal protein, rather than production of tumor masses, is the predominant manifestation. Recent studies have revealed chromosomal translocations in many of these patients, suggesting the presence of neoplastic clones.[171] Whether most of these clones would evolve into myeloma if the patients lived long enough can only be a matter for speculation.
Reactive Systemic Amyloidosis.
The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. This category was previously referred to as secondary amyloidosis because it is secondary to an associated inflammatory condition. The feature common to most of the conditions associated with reactive systemic amyloidosis is protracted breakdown of cells resulting from a wide variety of infectious and noninfectious chronic inflammatory conditions. At one time, tuberculosis, bronchiectasis, and chronic osteomyelitis were the most important underlying conditions, but with the advent of effective antimicrobial chemotherapy, the importance of these conditions has diminished. More commonly now, reactive systemic amyloidosis complicates rheumatoid arthritis, other connective tissue disorders such as ankylosing spondylitis, and inflammatory bowel disease, particularly Crohn disease and ulcerative colitis. Among these, the most frequent associated condition is rheumatoid arthritis. Amyloidosis is reported to occur in approximately 3% of patients with rheumatoid arthritis and is clinically significant in one half of those affected. Heroine abusers who inject the drug subcutaneously also have a high occurrence rate of generalized AA amyloidosis. The chronic skin infections associated with "skin-popping" of narcotics seem to be responsible for amyloidosis in this group of patients. Reactive systemic amyloidosis may also occur in association with non-immunocyte-derived tumors, the two most common being renal cell carcinoma and Hodgkin disease.
Hemodialysis-Associated Amyloidosis.
Patients on long-term hemodialysis for renal failure develop amyloidosis owing to deposition of β2-microglobulin. This protein is present in high concentrations in the serum of patients with renal disease and is retained in circulation because it cannot be filtered through the cuprophane dialysis membranes. In some series, as many as 60% to 80% of the patients on long-term dialysis developed amyloid deposits in the synovium, joints, and tendon sheaths.
Heredofamilial Amyloidosis.
A variety of familial forms of amyloidosis have been described. Most of them are rare and occur in limited geographic areas. The most common and best studied is an autosomal recessive condition called familial Mediterranean fever.[172] This is a febrile disorder of unknown cause characterized by attacks of fever accompanied by inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane. This disorder is encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins. It is associated with widespread tissue involvement indistinguishable from reactive systemic amyloidosis. The amyloid fibril proteins are made up of AA proteins, suggesting that this form of amyloidosis is related to the recurrent bouts of inflammation that characterize this disease. The gene for familial Mediterranean fever has been cloned, and its product is called pyrin (for its relation to fever). Although its exact function is not known, it has been suggested that pyrin is responsible for regulating acute inflammation, presumably by inhibiting the function of neutrophils.[173] The relationship of this mutation to the disease is not understood.
In contrast to familial Mediterranean fever, a group of autosomal dominant familial disorders is characterized by deposition of amyloid predominantly in the nerves—peripheral and autonomic. These familial amyloidotic polyneuropathies have been described in different parts of the world. As mentioned previously, in all of these genetic disorders, the fibrils are made up of mutant transthyretins (ATTR).
Endocrine Amyloid.
Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the stomach, and in the islets of Langerhans in patients with type II diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide).
Amyloid of Aging.
Several well-documented forms of amyloid deposition occur with aging.[174] Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their seventies and eighties). Because of the dominant involvement and related dysfunction of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias. The amyloid in this form is composed of the normal TTR molecule. In addition to the sporadic senile systemic amyloidosis, another form, affecting predominantly the heart, that results from the deposition of a mutant form of TTR has also been recognized. Approximately 4% of the black population in the United States is a carrier of the mutant allele, and cardiomyopathy has been identified in both homozygous and heterozygous patients. The precise prevalance of patients with this mutation who develop clinically manifest cardiac disease is not known.
Figure 6-53 Structure of an amyloid fibril, depicting the β-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified from Glenner GG: Amyloid deposit and amyloidosis. The β-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
Direct dermal infiltration can produce subcutaneous nodules and plaques. Classically described as smooth, waxy, yellowish lesions, these are uncommon and more often appear hemorrhagic. They are generally found on flexor surfaces, the face, and the buccal mucosa (Fig. 2). Cutaneous nodules can be demonstrated to follow the path of blood vessels within the skin [2]. Direct skin infiltration with amyloid can produce the appearance of scleroderma on the face, hands, and feet. Rarely, infiltrative nodular lesions may coalesce to form gross distortion and enlargement or tumefaction
Purpura, petechiae, and ecchymoses occur commonly in the skin and mucous membranes. They are due to intracutaneous hemorrhage, the result of amyloid infiltrating and weakening blood-vessel walls. These lesions may occur spontaneously and are particularly common in skin folds such as the eyelids, axillae, umbilicus, and anogenital area. Periorbital purpura may arise after coughing, sneezing, performing proctoscopy, or the valsalva maneuver
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Direct dermal infiltration can produce subcutaneous nodules and plaques. Classically described as smooth, waxy, yellowish lesions, these are uncommon and more often appear hemorrhagic. They are generally found on flexor surfaces, the face, and the buccal mucosa (Fig. 2). Cutaneous nodules can be demonstrated to follow the path of blood vessels within the skin [2]. Direct skin infiltration with amyloid can produce the appearance of scleroderma on the face, hands, and feet. Rarely, infiltrative nodular lesions may coalesce to form gross distortion and enlargement or tumefaction
Raccoon Eyes: A I5-month-old girl was admitted to hospital with the complaints of bruising around the eyes for 10 days. She had one month history of abdominal pain and accompanied by fever and vomiting for one week. Physical examination demonstrated pallor, periorbital ecchymoses (raccoon eyes) and bilaterally mild proptosis (Fig. 1). She also had a left sided abdominal mass, which was 5 × 8 cm in diameter. The laboratory investigation revealed hemoglobin level 6g/dL, white cell count 10,000/mm3 and platelet count 34,000/mm3. Urinary vanillymandelic acid level was high. Bilateral bone marrow aspiration revealed infiltration with neuroblasts. Abdominal CT showed a left supra-renal mass (5 × 7 cm in diameter), which was diagnosed as a neuroblastoma on histopathologic examination.
The metastatic involvement of the periorbital tissues. has been described and the resultant proptosis and orbital ecchymosis has been given the tag of ‘raccoon eyes’. Orbital metastases can be found in up to 20% of children with stage IV neuroblastoma. The raccoon eyes appearance associated with neuroblastoma is probably related to obstruction of the palpebral vessels by tumor tissue in and around the orbis. There are a multitude of differential diagnoses for the presentation of periorbital edema and ecchymosis, e.g., child abuse or trauma, infection of the soft tissues associated with a spreading dental infection and an allergic reaction. Other systemic causes to be considered include myxoedema, other neoplasias such as lymphoma or haematological coagulopathies such as haemophilia.
Notice the large hyaline masses arranged diagonally across the screen. The upper left and the lower right areas of the field are occupied by normal white pulp. Amyloidosis of the spleen is seen in two forms - the sago spleen in which amyloid depositis are limited to the follicles, and the lardaceous spleen in which amyloid is deposited in the walls of the splenic sinusoids and spares the follicles. It is not clear which form is seen in this picture.
Notice the large hyaline masses arranged diagonally across the screen. The upper left and the lower right areas of the field are occupied by normal white pulp. Amyloidosis of the spleen is seen in two forms - the sago spleen in which amyloid depositis are limited to the follicles, and the lardaceous spleen in which amyloid is deposited in the walls of the splenic sinusoids and spares the follicles. It is not clear which form is seen in this picture.
(A) The amyloid appears pink and is localized to the perifollicular zone. (B) The identical area exhibits green birefringence in polarized light. Amyloid is indicated by arrows.
Lugol’s Iodine: Mahagany brown, and treatment with 10% H2SO4 turns blue.
1% aqueous Methyl violet (5minutes) and differentiated with 1% acetic acid – Oink to red
Sirius red: similar to congo red. It’s an alternative.
Toludene blue: Dark red polariazation.
Thioflavine-T&S: bright red fluorescenece
Alcian blue: green.
Cong red: red with polarized light, apple green birefringence.
Amyloidosis, Lymphnode, Lugol's Reaction:
left: Positive Lugol reaction in node with amyloidosis. right: Negative Lugol reaction in normal myometrium.
A slice of the affected node (left) was treated for less than a minute in Lugol's solution. At right is a piece of normal myometrium treated similarly. The amyloid in the node reacts so strongly, it is almost black.