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WILLIAM'S HEMATOLOGY > 107 Immunoglobulin Light Chain Amyloidosis > Flashcards

107 Immunoglobulin Light Chain Amyloidosis Flashcards

1
Q

Common to all forms of amyloidosis, the deposits bind _______ dye and demonstrate ______ birefringence under polarized light.

A

Congo red dye

Green birefringence

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2
Q

Amyloid deposits are always (intracellualr, extracellular) and, under the light microscope, appear amorphous

A

Extracellular

They appear pink when viewed with standard hematoxylin and eosin staining.

Under the electron microscope, they are rigid, linear, nonbranching fibrils of 9.5-nm diameter.

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3
Q

Inherited forms of amyloidosis are generally composed of _________________ but can also be a consequence of point mutations in apolipoprotein, fibrinogen, and gelsolin.

A

Mutant transthyretin (TTR)

AA amyloidosis (secondary) can be the consequence of sustained inflammation but can also be inherited as it is in familial Mediterranean fever.

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4
Q

Previously referred to as senile systemic amyloidosis, primarily a cardiac disorder, caused by deposition of wild-type transthyretin as amyloid material in predominantly male patients over the age of 60 years

A

ATTRwt

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5
Q

The only form responsive to chemotherapy

A

AL amyloidosis

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6
Q

Nomenclature of Amyloidosis: Subunit Protein

AL or AH:
AA:
ATTR (wild type):
ATTR (mutant):
A lect 2:
A Ins:
A fib:
A B-2M:

A

AL or AH: Immunoglobulin heavy or light chain
AA: Secondary serum amyloid A
ATTR (wild type): Senile systemic transthyretin
ATTR (mutant): Familial transthyretin
A lect 2: Leukocyte chemotactic factor; No mutation found
A Ins: Insulin localized to injection sites
A fib: Fibrinogen Aα-2 mutation
A B-2M: β2 microglobulin, Chronic dialysis

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7
Q

Nomenclature of Amyloidosis: Clinical Organ Involvement

AL or AH:
AA:
ATTR (wild type):
ATTR (mutant):
A lect 2:
A Ins:
A fib:
A B-2M:

A

AL or AH: Heart, Kidney, Liver, Nerve
AA: Kidney, Gastrointestinal, Thyroid
ATTR (wild type): Heart, Carpal tunnel
ATTR (mutant): Heart, Nerve
A lect 2: Kidney
A Ins: Skin
A fib: Kidney
A B-2M: Soft tissue, joints, Spine

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8
Q

Light-chain amyloidosis represents approximately _____% of all amyloid patients seen at the Mayo Clinic, and immunoglobulin heavy-chain amyloidosis represents ______% of all patients.

A

Light-chain amyloidosis 52%

Heavy-chain amyloidosis <1%

The immunoglobulin light chains found in amyloid deposits usually range from 8 kD–15 kD.

In light-chain amyloidosis, the κ to λ ratio is 1:3

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9
Q

Subgorup of light chains found exclusively in patients with light-chain amyloidosis.

A

λVI

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10
Q

TRUE OR FALSE

Overt myeloma with true CRAB criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is common in light-chain amyloidosis.

A

FALSE

Overt myeloma with true CRAB criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is uncommon in light-chain amyloidosis.

Patients with AL amyloidosis are classified into those patients with myeloma and those without myeloma.

The percentage of plasma cells present in the marrow at the time of diagnosis is prognostic and predicts outcome in patients with AL amyloidosis.

Patients who do not have myeloma at presentation have little chance of developing myeloma later in the course of the disease.

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11
Q

Genetic abnormality seen in half of amyloidosis patients and appears to confer bortezomib resistance and an inferior outcome

A

translocation t(11;14)

The plasma cells in the marrow of patients with AL amyloidosis tend to be nonproliferative and frequently lack the genetic abnormalities that are typically seen in myeloma

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12
Q

TRUE OR FALSE

Only 1% of patients with AL amyloidosis are under the age of 40 years.

A

TRUE

Only 1% of patients with AL amyloidosis are under the age of 40 years.

This age group regularly can be seen with secondary systemic amyloidosis

The majority of patients with light-chain amyloidosis are males (66%), unlike myeloma, where the male-to-female ratio is 52:48.

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13
Q

Frequently cited as a diagnostic finding and, when present, is useful but is only seen in 15% of patients

A

Periorbital purpura

Enlargement of the tongue is seen in approximately one person in eight

Hepatomegaly is seen in approximately 20% of patients and is caused by direct infiltration of the liver

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14
Q

Periarticular infiltration of the shoulders is called the

A

Shoulder pad sign

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15
Q

Screening for light-chain amyloidosis

A

Immunoelectrophoresis and immunofixation of both serum and urine

Immunoglobulin free light-chain assay (both κ and λ) of serum.

Systemic AL amyloidosis is a plasma cell neoplasm, and 99% of patients will have a detectable abnormality of one of these three tests, reflecting their synthesis by a clonal population of plasma cells in the marrow

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16
Q

Screening for light-chain amyloidosis is recommended when a patient is seen with any of the following clinical syndromes:

A
  • Nephrotic-range proteinuria with any serum creatinine level;
  • Infiltrative cardiomyopathy or heart failure with preserved ejection fraction. A normal ejection fraction does not exclude AL amyloidosis. The only symptom may be exertional fatigue;
  • Hepatomegaly or alkaline phosphatase elevation without specific imaging abnormalities;
  • A mixed axonal demyelinating peripheral neuropathy, sensory and/or motor and/or autonomic, particularly when associated with a monoclonal gammopathy; and/or
  • A patient with myeloma or MGUS with unusual symptoms that are not typical or consistent with myeloma CRAB criteria, particularly unexplained fatigue.
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17
Q

If a systemic plasma cell neoplasm and an immunoglobulin light chain cannot be confirmed, the three possibilities are:

A
  • The patient does not have amyloidosis,
  • The patient does not have systemic AL amyloidosis, or
  • The amyloidosis is not immunoglobulin light chain in type and reflects a different protein subunit, the most common being ATTRwt cardiac amyloidosis.
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18
Q

Most commonly involved organ in amyloidosis

A

Kidney

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19
Q

A critically important screening test used for prognostication and staging

A

Free light-chain assay

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20
Q

TRUE OR FALSE

A screening serum protein electrophoresis is insufficient as a screening technique because a visible M-spike is seen in less than half of patients because of the high prevalence of light-chain proteinemia.

A

TRUE

A screening serum protein electrophoresis is insufficient as a screening technique because a visible M-spike is seen in less than half of patients because of the high prevalence of light-chain proteinemia.

Finding a monoclonal protein in the serum or in the urine of a patient with heavy albuminuria often obviates the need for a renal biopsy.

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21
Q

A patient with a free light chain in the serum or urine and proteinuria can have only one of three disorders:

A

(1) myeloma cast nephropathy
(2) light-chain amyloidosis, or
(3) Randall-type immunoglobulin deposition disease (κ).

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22
Q

Required to confirm the diagnosis of AL amyloidosis before therapy can commence

A

Biopsy

Although imaging of amyloid deposits with various radionuclides, most notably antiserum amyloid P component, continue to be explored and used in practice, they are not a substitute for histologic confirmation of the presence of AL amyloidosis

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23
Q

Biopsy of choice in AL

A

Subcutaneous fat aspiration
Marrow biopsy

The fat aspiration is positive in three-fourths of patients with amyloidosis.

Congo red staining of marrow blood vessels can detect amyloid deposits in half of patients with AL amyloidosis.

At the Mayo Clinic, combining the two techniques (marrow and fat-pad aspirate), enables the diagnosis in 85% of cases.

If the clinical suspicion of AL amyloidosis is strong and these biopsies are negative, it is appropriate to biopsy the affected organ.

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24
Q

Test to determine the protein subunit involved

A

Laser capture of the amyloid deposit followed by mass spectroscopic analysis

For patients who have ATTR amyloidosis, is that tissue mass spectroscopy not only identifies the protein in most instances, but may also indicate whether the protein is wild-type or mutant

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25
Q

Forms of systemic amyloidosis for which systemic chemotherapy is contraindicated

A

Fibrinogen A-α amyloidosis, amyloid caused by apolipoprotein-A1, apolipoprotein-A4, and gelsolin

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26
Q

Kidney involvement is seen in _____% of patients with immunoglobulin light-chain amyloidosis.

A

61%

It is conspicuously absent in the majority of patients with ATTR amyloidosis until late in the disease.

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27
Q

Renal involvement is virtually universal in what types of amyloidosis

A

Systemic AA amyloidosis
ALect2 amyloidosis
Alipoprotein amyloidosis
A-fibrinogen α amyloidosis

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28
Q

Typical feature of renal amyloidosis

A

Nephrotic syndrome: nephroticrange proteinuria, hypoalbuminemia, hyperlipidemia, and edema

29
Q

TRUE OR FALSE

One-half of patients with renal amyloidosis will ultimately require renal replacement therapy

A

FALSE

One-third of patients with renal amyloidosis will ultimately require renal replacement therapy

30
Q

The best predictor of which patients are most likely to require dialysis

A

Estimated GFR (eGFR) and level of urinary protein loss at the time of presentation

31
Q

The best method for prevention of dialysis

A

Effective therapy of the underlying plasma cell neoplasm

32
Q

TRUE OR FALSE

The correlation between the amount of amyloid seen in a renal biopsy and the degree of renal dysfunction is poor.

A

TRUE

The correlation between the amount of amyloid seen in a renal biopsy and the degree of renal dysfunction is poor.

Patients who progress to ESRD but who achieve complete hematologic response can be candidates for renal transplantation

33
Q

The most common cause of death in patients with renal amyloidosis

A

Progressive cardiac dysfunction from amyloid cardiomyopathy

34
Q

Type of cardiomyopathy in cardiac amyloidosis

A

Restrictive cardiomyopathy

Restrictive cardiomyopathy caused by amyloid infiltration results in poor relaxation (so-called “stiff heart syndrome”) and poor filling during diastole, so that the ventricular chamber has a low end-diastolic volume, which results in reduced stroke volume and a reduced cardiac output.

This represents a classic example of heart failure with preserved ejection fraction.

35
Q

Cardiac amyloid is found in about 45% of patients at diagnosis and is responsible for nearly _____% of deaths.

A

90%

36
Q

Diagnosis of cardiac amyloid

Most useful test for the imaging and diagnosis of amyloid

A

Echocardiography with doppler flow studies and cardiac strain studies

It is not particularly useful in terms of the serial monitoring of patients for response or progression after treatment.

37
Q

Echocardiographic clues of cardiac amyloidosis

A

Thickening of the right ventricle, atrial systolic failure, and reduction in left ventricular chamber size

Late consequences of cardiac involvement include valvular thickening and valvular regurgitation.

It is important to recognize that surgical repair of a valve will not result in meaningful improvement in the patient’s aerobic capacity.

38
Q

When light-chain testing is negative, the possibility of __________________ should be considered.

A

ATTRwt cardiac amyloidosis

Patients over the age of 60 years, predominantly men, half of whom will also have bilateral carpal tunnel syndrome

39
Q

Imaging in ATTRwt cardiac amyloidosis

A

Echocardiography, magnetic resonance imaging (MRI), or technetium pyrophosphate scanning

40
Q

A septal thickness greater than ____ mm would be rare with hypertensive cardiomyopathy and would be limited to either amyloidosis or hypertrophic cardiomyopathy

A

15 mm

Interestingly, the degree of cardiac infiltration in ATTRwt amyloidosis and familial amyloid cardiomyopathy is substantially greater than that seen in AL amyloidosis

AL amyloidosis: larger than 18 mm will generally have significant disability related to cardiac failure

ATTR amyloidosis, both mutant and wildtype, will frequently have septal thicknesses in the range of 25 mm with minimal symptomatology.

41
Q

Highly sensitive in the diagnosis of cardiac amyloidosis

A

Endomyocardial biopsy

If five specimens are taken, recognition of the diagnosis is virtually certain

42
Q

The mainstay of management for cardiac amyloidosis

A

Diuretic therapy

43
Q

Gene involved in familial amyloid cardiomyopathy

A

TTRVal122Ile

44
Q

Play an important role in the prognosis of cardiac amyloidosis as well as in its functional assessment

A

Cardiac biomarkers: B-natriuretic peptide and troponin

All patients who present with amyloidosis, regardless of whether cardiac disease is suspected, should have cardiac biomarkers performed.

45
Q

Cardiac amyloidosis

Mayo (2012) staging involves the assignment of a point for any of the following characteristics:

A
  • Difference between the involved and uninvolved free light chain of greater than 180 mg/L
  • A high sensitivity (hs) cardiac troponin T level >40 ng/L
  • An NT-proBNP of greater than 1800 pg/mL.
46
Q

Marker used to define response and progression and have supplanted the use of serial echocardiography to assess changes over time, both in following the natural history as well as assessing response to therapeutic interventions

A

NTproBNP

47
Q

MRI finding specific for cardiac amyloidosis.

A

Delayed subendocardial enhancement

48
Q

A sensitive marker for the presence of ATTR amyloidosis

A

Technetium pyrophosphate

49
Q

Presentation of patients with liver amyloidosis

A

Hepatomegaly and elevation of the serum alkaline phosphatase, with normal or near-normal transaminases and bilirubin

Liver infiltration caused by amyloid can be seen in up to 15% of patients with light-chain amyloidosis.

Half of the patients with hepatic amyloidosis have renal amyloidosis, which dominates the clinical syndrome.

Portal hypertension and ascites are uncommon.

50
Q

Diagnosis of liver amyloidosis

A

Fat aspiration and marrow biopsy

But a liver biopsy is safe and does not have a higher risk of bleeding complications than in other patients with liver disease.

51
Q

Amyloid deposits in what part of the nervous system

A

Vasa nervorum

Causes a mixed axonal and demyelinating peripheral neuropathy.

The neuropathy is symmetric, tends to ascend beginning in the toes, and eventually involves the upper extremities

52
Q

Nervous System Amyloidosis

Approximately half of the patients will have an associated ____________________ , and approximately one-fourth will have associated ________________________

A

Carpal tunnel syndrome

Autonomic features

53
Q

The progression of amyloid neuropathy is slow, and it is common to have delays of ____ years before a diagnosis is established.

A

2–3 years

54
Q

TRUE OR FALSE

Electromyography is not particularly useful in the early diagnosis because amyloid preferentially affects the small unmyelinated fibers of the extremities, which are not well assessed with standard electrodiagnostic studies.

A

TRUE

Electromyography is not particularly useful in the early diagnosis because amyloid preferentially affects the small unmyelinated fibers of the extremities, which are not well assessed with standard electrodiagnostic studies.

55
Q

The prognosis in amyloidosis is determined by two factors

A

Extent of cardiac involvement

Plasma cell burden

Cardiac involvement measured by the use of cardiac biomarkers.

Plasma cell burden: difference between the involved and uninvolved light chains in the serum (dFLC)

56
Q

Parameters used to stage amyloidosis

A

NT-proBNP, troponin, and free light chain

  • hs troponin T level equal to or greater than 40 ng/L
  • NT-proBNP greater than 1800 pg/mL
  • dFLC greater than 180 mg/L

Alternatively, one can use the Mayo 2014 system with the European modification, which also gives four groups, but uses only the troponin and the NT-proBNP.

The Mayo 2004 system is especially helpful for predicting the risk of early death.

57
Q

Two parameters to assess response

A

Hematologic response
Organ function

58
Q

Hematologic response

A
  • Complete remission : negative immunofixation of serum and urine and a normal immunoglobulin free light-chain ratio
  • Very good partial response : dFLC less than 40 mg/L
  • Partial response : 50% decrease from baseline in the dFLC
  • Failure to respond

Light-chain assessment is not only the ideal method for measuring response because of the rapid decline in levels, but it is better than the intact immunoglobulin as a measure of response when both are present.

59
Q

Renal response

A
  • Partial renal response: 31% to 60% decrease in 24-hour urine protein volume
  • Very good partial response: more than 60% reduction in proteinuria
  • Complete renal response: less than 200 mg protein lost within 24 hours
  • Progression: 50% increase in urinary protein loss to at least 1 g/day or a 25% worsening of creatinine clearance
60
Q

Cardiac response

A
  • Partial response: A 31% to 60% reduction in the NT-proBNP— a minimum of 300 ng/L in patients whose baseline NT-proBNP is greater than 650 ng/L
  • Very good partial response: more than a 60% reduction
  • Complete cardiac response: NT-pro BNP lower than 400 pg/mL
  • Cardiac progression : 30% increase in NT-proBNP, a minimum increase of 300 ng/dL

An improvement in the New York Heart Association class by two stages from a IV to II or III to I also is considered a response.

61
Q

Liver repsonse

A
  • Response: 50% reduction in the abnormal alkaline phosphatase value
  • Progression : 50% increase of alkaline phosphatase above the lowest recorded value

Currently, consensus criteria to define response in soft tissues such as the gastrointestinal tract, the tongue, the lung, or peripheral nerves do not exist for lightchain amyloidosis.

62
Q

Standard of therapy for amyloidosis

A

Melphalan and prednisone
Melphalan and dexamethasone

Melphalan and prednisone: the response rate never exceeded 25%

Melphalan and dexamethasone: very low therapy-related mortality and can be administered to patients with cardiac and renal failure as well as the to the physically frail

Melphalan should be avoided in transplant-eligible patients because it may impair stem cell collection

63
Q

TRUE OR FALSE

Autologous stem cell transplant been proven to be superior to conventional chemotherapy

A

FALSE

Autologous stem cell transplant has not been proven to be superior to conventional chemotherapy

64
Q

Autologous stem cell transplant in Amyloidosis

To reduce treatment-related mortality, relatively stringent inclusion criteria should be adopted

A
  • Biologic age less than 70 years
  • Serum creatinine lower than 1.8 mg/dL
  • Hs troponin T less than 75 ng/L
  • Aystolic blood pressure higher than 90 torr

To optimize stem cell collection, transplant candidates should not be exposed to melphalan beforehand, and stem cells are frequently mobilized without using cytotoxic chemotherapy.

65
Q

Although it is common practice not to use induction chemotherapy before stem cell transplantation, patients with high plasma cell counts in the marrow (>10%) merit pretransplantation induction chemotherapy, typically with

A

CyBorD

66
Q

Predictors of outcome after stem cell transplantation

A

Cardiac biomarkers, NTproBNP, and troponin

67
Q

Immunomodulator drug that can increase the level of NT-proBNP and may actually aggravate heart failure

A

Lenalidomide

The typical dose of lenalidomide used to treat myeloma is not well tolerated by patients with AL amyloidosis and treatment should be initiated at no more than 15 mg daily.

68
Q

PI that resulted 36% cardiac toxicity but has been reported to be beneficial in patients with AL amyloidosis neuropathy

A

Carfilzomib

WILLIAM'S HEMATOLOGY (89 decks)

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