amyloidosis

Question 1

what is the amyloid?

Answer 1

pathologic proteinaceous substance de3posited between cells in various tissues and organs of the body in a wide variety of clinical settings

Question 2

what are the 2 parts of amyloid?

Answer 2

1) Fibrillar component (90–95% of amyloid): β-sheet fibrils, Varies depending on the underlying disease.
2) A nonfibrillar component is usually the same in all types of amyloid and makes up 5–10% of amyloid. pentagonal glycoprotein (Amyloid P component), which is derived from a circulating serum protein called serum amyloid P (SAP).
3) Proteoglycans

Question 3

what is -pleated sheets?

Answer 3

In Amyloidosis, a specific precursor protein pathologically misfolds from its physiologic tertiary structure into a more linear shape dominated by beta-pleated sheets

Question 4

what is amyloid fibril?

Answer 4

Misfolded protein aggregates into oligomers, eventually forming insoluble amyloid fibrils that deposit extracellularly in tissues

Question 5

how amyloid leads to organ dysfunction?

Answer 5

Both the circulating oligomers, which are cytotoxic, and the fibrils, which cause distortion of the tissue architecture to result in pressure atrophy of adjacent cells, lead to organ dysfunction.

Question 6

few proteins are involved in various amyloid diseases. True/False.

Answer 6

False.

• > 35 different proteins implicated in various amyloid diseases:
  1) hereditary or nonhereditary
  2) localized or systemic
  3) with different organ involvement and prognosis

Question 7

On H&E, appears as

Answer 7

as amorphous, eosinophilic hyaline extracellular substance

Question 8

under polarized light amyloid displays

Answer 8

• Apple-green birefringence

- -s the result of crossed-ß-pleated sheet configuration of amyloid.

Question 9

what stain is used to stain amyloid?

Answer 9

Congo red stain

imparts a pink or red color to amyloid deposits. It binds to amyloid by hydrogen bonds.

Question 10

how congo red stain bind to amyloid?

Answer 10

by hydrogen bonds

Question 11

Immunohistochemistry is used in the diagnosis of amyloidosis.True/False.

Answer 11

True

Question 12

what is the classification of amyloidosis?

Answer 12

1)Systemic – generalized, involving several organ systems
•Primary amyloidosis – associated with some immunocyte dyscrasia
•Secondary amyloidosis – a complication of underlying chronic inflammatory or destructive tissue process
2)Localized – deposits in a single organ, eg heart
3Hereditary or familial amyloidosis – separate yet distinctive pattern of organ involvement, that is usually systemic

Question 13

Current classification systems of amyloidosis are based on…

Answer 13

the protein that produces the majority of the deposits; usually abbreviated, starting with the letter ‘A’.
Some of these are biochemically distinct proteins (eg Transthyretin (TTR), or β2 macroglobulin (TTR))

Question 14

what is the primary vs secondary amyloidosis?

Answer 14

types of systemic amyloidosis.

1) Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis
2) secondary amyloidosis (i.e., secondary to chronic inflammatory conditions)

Question 15

list types of systemic amyloidosis

Answer 15

1) Light-chain amyloidosis
2) reactive systemic amyloidosis
3) hemodialysis associated amyloidosis
4) Familial Mediterranean Fever
5) Familial amyloidotic neuropathies
6) systemic senile amyloidosis

Question 16

what are the major fibril proteins called of these types of systemic amyloidosis respectively

1) Light-chain amyloidosis
2) reactive systemic amyloidosis
3) hemodialysis associated amyloidosis
4) Familial Mediterranean Fever
5) Familial amyloidotic neuropathies
6) systemic senile amyloidosis

Answer 16

1) AL
2) AA
3) Aβ2M
4) AA
5) ATTR
6) ATTR

Question 17

what are the chemically related precursor proteins for these types of systemic amyloidosis respectively

1) Light-chain amyloidosis
2) reactive systemic amyloidosis
3) hemodialysis associated amyloidosis
4) Familial Mediterranean Fever
5) Familial amyloidotic neuropathies
6) systemic senile amyloidosis

Answer 17

1) Light chains of immunoglobulins (particularly kappa chain)
2) SAA (Serum amyloid-associated protein )
3) β2-microglobulin
4) SAA
5) Transthyretin
6) Transthyretin

Question 18

what is the β2-microglobulin?

Answer 18

A low molecular weight structural component of major histocompatibility complex type 1 (MHC I). It is freely filtered by the glomerulus. In patients who undergo long-term hemodialysis therapy, it can accumulate and aggregate as amyloid fibrils in joints because the hemodialysis filtration membrane does not allow beta-2 microglobulin to pass through.

Question 19

what are the light chains of immunoglobulins?

Answer 19

component of immunoglobulin, which consists of four different proteins. Two of these proteins are larger than the other two and are called heavy chains. The two smaller proteins are referred to as light chains, which themselves can be one of two types: kappa or lambda. Production of excess light chains (usually due to hematopoietic aberrations) occurs in diseases such as primary systemic amyloidosis and multiple myeloma.

Question 20

what s the transthyretin?

Answer 20

A transport protein synthesized by the liver that carries thyroxine and the retinol-RBP complex. Conditions that result in the accumulation of transthyretin include senile cardiac amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy.

Question 21

what are the types of localized amyloidosis

Answer 21

1) senile cerebral
2) endocrine amyloidosis
3) isolated atrial amyloidosis
4) prion diseases

Question 22

endocrine amyloidosis includes…

Answer 22

1) Islet cella amyloidosis
2) medullary carcinoma of the thyroid
3) Amyloid at the insulin injection site (AIns)

Question 23

what proteins are involved in localized types of amyloidosis?

1) senile cerebral
2) isolated atrial amyloidosis
3) prion diseases
4) Islet cella amyloidosis
5) medullary carcinoma of the thyroid
6) Amyloid at the insulin injection site (AIns)

Answer 23

1) Aβ derived from APP
2) AANF → increased risk of atrial fibrillation (derived from Atrial Natriuretic peptide)
3) PrPSc derived from normal, not misfolded PrP
4) Islet amyloid polypeptide (IAPP) → amylin deposition in pancreatic islet
5) Procalcitonin (ACal)
6) AIns

Question 24

what are the types of hereditary amyloidosis?

Answer 24

1) Familial amyloid cardiomyopathy
- Mutated transthyretin (ATTR)
2) Familial amyloid polyneuropathy (FAP)
- Mutated transthyretin (ATTR)
3) Familial Mediterranean fever (FMF)
- AA amyloid protein

Question 25

what are the 3 most common types of amyloidosis?

Answer 25

• AL (amyloid light chain) is due to an overproduction of immunoglobulin light chains derived from plasma cells
• AA (amyloid-associated) is due to continuous overproduction of acute-phase proteins in chronic inflammation
• Aβ amyloid is found in the cerebral lesions of Alzheimer’s disease

Question 26

describe AL amyloidosis

Answer 26

1)Most common form of amyloidosis in developed nations
2)Etiology: associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenstrom macroglobulinemia)
-Many patients have some form of a monoclonal B cell proliferation, which synthesizes abnormal amounts of immunoglobulin.
3)Pathophysiology: increased production of the light chains of immunoglobulins by plasma cells → deposition of AL (amyloid light chain) protein in various organs
4)Clinical presentation: rapidly progressive clinical course
–Heart: restrictive cardiomyopathy, atrioventricular block
–Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
–Tongue: macroglossia → obstructive sleep apnea
–Autonomic nervous system: autonomic neuropathy
–Gastrointestinal tract: malabsorption
Bleeding disorders

Question 27

describe Multiple Myeloma as a cause of primary amyloidosis

Answer 27

• -malignancy of white blood cells characterized by overproduction of either one or multiple lineages of B lymphocytes. The proliferation of B lymphocytes and their associated proteins (antibodies) causes decreased kidney function, hypercalcemia, anemia, and disruption in bone metabolism that manifests as bone pain. Patients also report foamy urine due to Bence Jones proteinuria.
• -amyloidosis is seen in approx. 5-15% of patients with multiple myeloma.
• -the increased amounts of immunoglobulin will produce an M protein spike on serum electrophoresis.
• -kidneys are heart are most often involved.
• -patients with myeloma and AL amyloidosis generally follow an unremitting and ultimately fatal course, either from malignancy or from cardiac/renal complications of amyloid.
• -some treatment options are available including bone marrow transplant or chemotherapy.

Question 28

AL amyloid is derived from?

Answer 28

light chains of immunoglobulins (kappa chains)

Question 29

describe AA (reactive) amyloidosis

Answer 29

1) etiology: secondary disease
- -Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)
- -Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)
- -Certain tumors (e.g., renal cell carcinoma, lymphomas)
2) Pathophysiology: chronic inflammatory process → increased production of acute-phase reactant SAA (serum amyloid-associated protein) by liver → deposition of AA (amyloid-associated) protein in various organs ( Deposits are systemic in distribution)
- -SAA is a normal plasma protein synthesized in the liver, under influence of cytokines such as IL6 and IL1, as part of the physiologic acute phase response.
3) Clinical features
- -Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
- -Adrenal glands: primary adrenal insufficiency
- -Liver and spleen: hepatomegaly, splenomegaly
- -Gastrointestinal tract: malabsorption
- -arrhythmias due to amyloid deposition on the conductive system, restrictive cardiomyopathy
4) If untreated, it is associated with significant mortality due to end-stage renal disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding

Question 30

in secondary amyloidosis, amyloid deposition is systemic or localized?

Answer 30

systemically

Question 31

which cytokines influence SAA synthesis by the liver?

Answer 31

IL6 and IL1

Question 32

what is the common cause of death in AA amyloidosis?

Answer 32

end-stage renal disease

Question 33

what infections can cause AA amyloidosis?

Answer 33

Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)

Question 34

what are the kidney manifestations of systemic amyloidosis?

Answer 34

Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus

Question 35

Al amyloid deposit systematically or locally?

Answer 35

systematically

Question 36

which tumors produce endocrine amyloid

Answer 36

• Islet cell tumors of the pancreas.

* Thyroid medullary carcinoma

Question 37

what is nephrotic syndrome?

Answer 37

A combination of symptoms seen in various renal diseases that are associated with dysfunction of the renal filtration system. Characterized by massive renal loss of protein (> 3.5 g/day) resulting in edema and hypoalbuminemia, hyperlipidemia, hypercoagulability (antithrombin III deficiency), and an increased risk of infection (loss of immunoglobulins).

Question 38

what is a nephritic syndrome?

Answer 38

A syndrome characterized by glomerular damage, leading to hematuria, pyuria, water retention, and subsequent hypertension and edema. Can be caused by a variety of conditions, including autoimmune, hereditary, and infectious disease

Question 39

what is restrictive cardiomyopathy?

Answer 39

pathologic condition of the heart muscle characterized by decreased compliance and stiffening of atrium and ventricle walls. The most common causes are amyloidosis and myocardial fibrosis after cardiac surgery or radiation. Associated with signs of diastolic heart failure. Systolic ejection fraction is commonly preserved.

Question 40

what is the sago spleen?

Answer 40

a spleen which is affected with amyloid degeneration and in which the amyloid is deposited in the Malpighian corpuscles which appear in cross-section as gray translucent bodies resembling grains of sago

Question 41

what is the macroscopic appearance of the kidney affected by amyloidosis?

Answer 41

Large, pale, grey, firm.

Question 42

what is the microscopic appearance of the kidney affected by amyloidosis?

Answer 42

amyloid deposits principally in glomeruli and interstitial peritubular tissue, as well as walls of blood vessels. Eventual obliteration of the glomerulus.

Question 43

what is the macroscopic and microscopic appearance of spleen affected by amyloidosis?

Answer 43

• Moderate enlargement, pale, grey, waxy
• Microscopically deposits in splenic follicles (sago spleen) or involve the splenic sinuses in large sheet-like deposits (lardaceous spleen)

Question 44

what is the macroscopic and microscopic appearance of the liver affected by amyloidosis?

Answer 44

• Massive enlargement up to 9000g.
• Microscopic deposits in space of Disse, then hepatic parenchyma and sinusoids
• Trapped hepatocytes undergo compression atrophy and get replaced by amyloid

Question 45

what is the space of disse?

Answer 45

The plasma-filled space between the sinusoids and hepatocytes is called the perisinusoidal space (of Disse): contains hepatic stellate cells (Ito cells), which store vitamin A and are the main source of extracellular matrix production in liver injury (formation of scar tissue → fibrosis)

Question 46

what is the macroscopic and microscopic appearance of the heart affected by amyloidosis?

Answer 46

• Mild to moderate enlargement, grey pink subendocardial elevations especially in the atria
• Microscopically, deposits throughout the myocardium, first between myocardial fibers, then causing pressure atrophy

Question 47

what other organs are affected in systemic amyloidosis?

Answer 47

• Endocrine: Adrenals, thyroid, pituitary, pancreas (diabetes)
• GIT – may be identified on a rectal biopsy
• Tongue – macroglossia
• Synovial tissue – carpal tunnel syndrome
• Amyloid infiltrating myocardium

Question 48

what is carpal tunnel syndrome?

Answer 48

Peripheral neuropathy caused by chronic or acute compression of the median nerve by the transverse carpal ligament. Characterized by both sensory disturbances (pain, tingling, and numbness) and motor symptoms (weakness and clumsiness of the thumb) in the area innervated by the median nerve distal to the carpal tunnel.

1) The following risk factors are associated with CTS:
- -Previous fracture of the distal radius (most important risk factor)
- -Traumatic dislocation of the lunate
- -Manual work: increased risk in workers using vibrating tools or prolonged, forceful, and repetitive flexion/extension of the wrist
- -Rheumatoid arthritis and other types of chronic inflammation of the tendon sheaths
- -Pregnancy and puerperium: Recent studies show that CTS may affect up to 62% of pregnant women.
- -Obesity
- -Osteoarthritis
- -Diabetes with peripheral polyneuropathy
- -Hypothyroidism

Question 49

what is the diagnosis of amyloidosis?

Answer 49

• -A biopsy followed by confirmation with Congo Red staining is the most important tool in the diagnosis.
• -This is usually done in an organ suspected to be involved – e.g. kidney, gingival, rectal, or abdominal ‘fat pad’ biopsy
• -immunohistochemistry also can be used

Question 50

what is the survival of late with generalized amyloidosis

Answer 50

The outlook for patients presenting late with generalized amyloidosis is poor with a mean survival time of 1-3yrs after diagnosis

Question 51

what study should be performed for AL amyloidosis?

Answer 51

For AL, serum and urinary protein electrophoresis may be performed
Urine test for Bence-Jones proteins

Question 52

what is the birefringence?

Answer 52

• The splitting of a light wave into two unequally reflected waves by an optically anisotropic medium (double refraction
• Cross-β-pleated sheet conformation is responsible for the distinctive staining and birefringence of Congo red/Sirius red-stained amyloid

Question 53

what is the treatment of amyloidosis?

Answer 53

• -No definitive therapy exists
• -Adequate treatment of the underlying disease may stall disease progression.
• -If amyloidosis progresses rapidly (e.g., light chain amyloidosis): corticosteroids, melphalan
• -Prevention of AA-amyloidosis and consequent renal failure in patients with FMF: colchicine

Question 54

what is the melphalan?

Answer 54

A chemotherapeutic agent (alkylating agent, nitrogen mustard) typically used in the treatment of multiple myeloma and ovarian cancer. Common side effects include fatigue, myelosuppression, hypokalemia, and peripheral edema

Question 55

what is the Famillin Mediterranean Fever (FMF)?

Answer 55

1) Description: A hereditary autoinflammatory disorder characterized by recurrent, self-limiting fever attacks, serositis, and often other inflamed tissue. Patients do not experience any symptoms between attacks.
2) Epidemiology: mostly limited to individuals of eastern Mediterranean descent; most common inherited fever syndrome
3) Genetics: an autosomal-recessive mutation in the MEFV gene on chromosome 16
4) Clinical presentation: can vary greatly
- -All patients experience fever attacks lasting 1–3 days and recur over weeks to months.
- -Most patients (95%) experience abdominal pain and arthralgia (75%).
- -Other manifestations
- Chest pain (40%) Due to peritonitis and sometimes pericarditis
- -Scrotal pain Due to inflammation of the tunica vaginalis
- -Myalgia
- -Erysipeloid
5) The disorder often goes undiagnosed in patients with mild to moderate symptoms.
6) Patients often have an appendectomy scar from a past episode of FMF that was mistaken for acute appendicitis.
7) Complication: AA amyloidosis
8) Therapy: Prevention of AA amyloidosis through inhibition of granulocyte function: by colchicine

Question 56

what is the colchicine

Answer 56

an anti-inflammatory agent that inhibits microtubule polymerization. Primarily used in the treatment of acute gouty arthritis and FMF