Transcript HPI - iupui

AMYLOIDOSIS
When good proteins go bad
HPI
A 69 yo male complains: “I move so
slowly that I can’t play golf anymore”.
What questions would you like to ask
your patient?
HPI
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Pt complains of feeling weak and tired for about a year.
Pt unintentionally lost 20 pounds in the past 6 months.
Pt complains of one year of worsening dyspnea on exertion.
Pt complains of intermittent two-pillow orthopnea.
Pt admits that his legs have swelled up on occasion over the past
year.
Pt complains that his muscles have felt weak for the past year or so.
Pt complains of subjective fatigue and decreased mental acuity.
Pt complains of a mild sense of abdominal fullness for the past year
or so.
Pt complains of pain over his hips, and pain over his right ribs; this
came on slowly about three months ago.
Medical History
• Significant for hypertension, well-controlled with
a thiazide diuretic.
• Family history:
– Father was diabetic, and died of CHF at age 57.
– Mother was hypothyroid, and died of breast cancer at
66.
• Social History:
– Worked as a salesman for a tractor dealership. 20
pack-year smoking history, but quit five years ago.
Drinks socially. No illicit drugs.
Physical Exam (significant findings)
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Vitals:
– T 37ºC, HR 104, RR 16, BP 138/89
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Neurologic:
– Dysarthria – pt says this began insidiously in the last 18 months; denies history of stroke.
– Dysphagia – same time frame.
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HEENT:
– Macroglossia
– Mucosal pallor
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Chest:
– crackles over bilateral lung bases
– S4 heart sound
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Abdomen
– Scaphoid abdomen
– Liver edge is palpable 6 centimeters below the costal margin
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Extremity
– 2+ bilateral pitting edema
– 4+ strength
Differential Diagnosis of Anemia
• This patient is tachycardic and pale. By physical
diagnosis, we can guess that he is likely anemic.
• Differential Diagnosis: Can be broad.
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Iron deficiency anemia (chronic bleeding?)
Nutritional deficiency (vitamin B12, folate)
Malignancy
Blood dyscrasia
Autoimmunity
Hypersplenism
Infection
Red blood cell structural/metabolic defect
Initial Tests/Procedures
• Chem 10 (Na+, K+, HCO3-, Cl-, BUN, Cr,
Glucose, Ca++, Phosphate, Mg++)
• CBC with differential
• B-type Natriuretic Peptide – evaluates for
heart failure
• Liver Enzymes – detects liver damage
• X-rays of painful sites – investigate possibility
of malignancy
Tests/Procedures 1: Results
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Metabolic:
– Na+ 140 mEq/L
– K+ 5.2 mEq/L
– HCO3 16 mEq/L
– Cl- 88 mEq/L
– BUN 48 mg/dL
– Creatinine 3.0 mg/dL
– Glucose 100 mg/dL
– Ca++ 12.7 mg/dL
– Mg++ 2.0 mg/dL
– PO4 3.5 mg/dL
CBC:
– Hemoglobin: 7.0mg/dL, reticulocytes 0.02%
– Hematocrit: 21%
– WBC: 8,000/µL – 74% neutrophil, 20% lymph, 4% monocyte, 1% eosinophils, 1% basophils
– Platelet: 200,000/µL
BNP
– 650 pg/mL
Liver:
– AST 105U/L, ALT, 150U/L, Alk Phos 200U/L
WHICH OF THESE VALUES ARE ABNORMAL?
WHICH OF THESE VALUES ARE
ABNORMAL?
• Metabolic: (Abnormals are in red)
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Na+ 140 mEq/L (Normal ≈ 137-145 mEq/L)
K+ 5.2 mEq/L (Normal ≈ 3.5-5.0 mEq/L)
HCO3 16 mEq/L (Normal ≈ 22-26 mEq/L)
Cl- 88 mEq/L (Normal≈ 98-110 mEq/L)
BUN 48 mg/dL (Normal ≈ 7-21 mg/dL)
Creatinine 3.0 mg/dL (Normal ≈ 0.5-1.4 mg/dL)
Glucose 100 mg/dL (Normal ≈ 65-110 mg/dL)
Ca++ 12.7 mg/dL (Normal ≈ 8.9-10.4 mg/dL)
Mg++ 2.0 mEq/L (Normal ≈ 1.5-2.5 mEq/L)
PO4 3.5 mg/dL (Normal ≈ 2.4-4.1 mg/dL)
WHICH ARE ABNORMAL?
• CBC:
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Hemoglobin: 7.0 mg/dL (Normal male ≈ 13.2-16.2 mg/dL)
Reticulocytes 0.02% (Normal adult ≈ 0.5%-1.5%
Hematocrit: 21% (Normal male ≈ 40-52%)
WBC: 8,000/µL – 70% neutrophil, 24% lymph, 4% monocyte, 1%
eosinophils, 1% basophil. (Normal WBC ≈ 4,100-10,900/µL)
– Platelet: 200,000 (Normal 140,000-450,000/µL)
• BNP
– 650pg/dL (Normal <100 pg/dL; 650 pg/dL suggests moderate heart failure).
• Liver:
– AST 105, ALT, 150, Alk Phos 200.
• AST Normal ≈ 5-35 U/L
• ALT Normal ≈ 7-56 U/L
• Alk Phos Normal ≈ 38-126 U/L
LAB RESULTS, RECAP
• Patient has…
– Hypercalcemia
– Renal Failure
• Elevated BUN and creatinine; patient’s hyperkalemia and
anion gap metabolic acidosis are consistent.
• The BUN/Creatinine ratio is < 20, which suggests intrinsic
renal failure.
– Anemia
– Elevated Liver Enzymes
– Congestive Heart Failure
• Based on his labs, which category is first in your
differential?
Imaging – Patient’s Chest X-Ray
First, look at the patient’s clavicle. See
how the cortex is highly radiopaque
(white), and thick.
Next, look at the patient’s fourth rib in
the inset. Notice that the superior
surface of the rib looks scalloped, and
that the opacity of normal cortical bone
is not present. This is consistent with a
lytic lesion, or a pathologic process
causing localized bone loss. This patient
likely has a malignancy.
Imaging – Patient’s Abdominal X-Ray
Over here, notice that the
bone texture is not as
uniform. Rather, there
are sudden changes from
dark to light. These are
consistent with the
characteristic “punchedout” lytic lesions of
multiple myeloma.
First, appreciate the relatively
uniform “texture” of the bone
in this part of the pelvis. No
sudden changes in color.
Imaging – Patient’s Skull Film
This is a classic view of multiple myeloma. Note the punched-out lytic
lesions (arrow and others). The pathophysiology of these lesions
involves nests of tumor cells in the bone. Eventually, these lytic
lesions may result in pathologic fractures.
Lead Differential Diagnosis
• Given the constellation of abnormalities (calcium, renal, anemia,
bone disease), you should suspect multiple myeloma.
• Diagnostic criteria for multiple myeloma are:
– Characteristic clinical and lab abnormalities (CRAB)
– Bone marrow biopsy; generally has to show 10% or more plasma cells
– Monoclonal (M) protein in serum
• Multiple myeloma alone, however, can’t account for his other
problems, including heart failure, his hepatomegaly with elevated
liver enzymes, his macroglossia, dysphagia, or dysarthria.
• Is there a possible link between his likely myeloma and his other
problems? The timing of all these problems is suspicious!
• What other diagnostic tests would you order?
More tests?
• Confirm Myeloma
– Serum Protein Electrophoresis
– Bone Marrow Biopsy
• Further Investigation
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Liver biopsy
Renal biopsy
Echocardiogram
Heart biopsy, if echocardiogram suggests certain
cardiomyopathies.
– Electrocardiogram
Intro to Serum Protein Electrophoresis
Albumin
Alpha
Beta
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5 peaks typically observed; each corresponds to a group of plasma proteins.
Albumin: most common protein in human serum
Alpha-1: 90% alpha-1 antitrypsin; also thyroid-binding globulin and transcortin
Alpha-2: alpha-2 macroglobulin, ceruloplasmin and haptoglobin
Beta:
– Beta-1: transferrins
– Beta-2: beta-lipoprotein
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Gamma
Gamma: immunoglobulins and C-reactive protein
Serum Protein Electrophoresis – Our
Patient
• Serum Protein Electrophoresis
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PATIENT – note the gamma spike.
The gamma spike corresponds to an excess of
immunoglobulin in this patient’s serum, made by
the myeloma cells. Further analysis showed that
this immunoglobulin was monoclonal.
Confirming Myeloma: Bone Marrow
Biopsy
You can tell these are plasma cells
by…
Clock-face chromatin, arranged
densely around the periphery of the
nucleus.
“Perinuclear hof”, or area of
clear cytoplasm near the nucleus.
The pathology report returns, stating that the patient’s
bone marrow contains 21% plasma cells, establishing a
diagnosis of multiple myeloma.
Next Steps…
Now to look at the liver, kidney, and heart
findings…is there a link between his cardiac
findings and his myeloma?
BIOPSY RESULTS
Liver biopsy.
“Fluffy” pink
amyloid; this
consists of betapleated protein
sheets.
Remaining hepatocytes
BIOPSY RESULTS
Heart biopsy
Myocytes
Amyloid
BIOPSY RESULTS
Renal Biopsy
Glomerulus with mesangial deposits
of amyloid. A unique property of
amyloid is that it stains well with
Congo Red dye.
Remember: No Congo red staining,
no amyloid!!
To confirm…
Renal biopsy, stained with
Congo Red.
Under polarized light, the stain
displays apple-green
birefringence.
Biopsy Discussion
The biopsy establishes the link between the patient’s
myeloma and his other problems.
The patient is experiencing amyloidosis, which is an
uncommon, but devastating systemic manifestation of
this malignancy, in which abnormal protein, or
“amyloid” aggregates form in numerous organs.
The amyloid in this case likely consists of monoclonal light
chains made by the malignant plasma cells.
Results Discussion
• CARDIAC TESTING:
• Patient’s echocardiogram demonstrates
severe diastolic dysfunction.
• This result is consistent with the tissue
diagnosis of amyloidosis, and with his clinical
picture of heart failure.
• Pathophysiology Note: Amyloidosis stiffens
the ventricles, impairing their ability to fill
properly during diastole.
Tests and Procedures: Results
• 2 months later patient yields the following EKG. You
can tell it’s a complete heart block because the P
waves are not paired with QRS complexes.
Amyloidosis patients are susceptible to
conduction abnormalities due to heart
tissue disruption by amyloid.
Our Patient and his Diagnosis
• Multiple Myeloma with 2º AL amyloidosis.
– Malignancy of Plasma Cells
– MM is associated with AL amyloidosis in 20% of
biopsy-proven cases.
– Most commonly, AL amyloidosis happens as a primary
disease, or secondary to other plasma cell dyscrasia
syndromes such as MGUS or Waldenström
macroglobulinemia.
– The amyloid consists of fibril-forming or nonfibrillar
aggregates of monoclonal immunoglobulin light
chains made by the malignant cells.
Amyloidosis
• Defined as extracellular deposition of protein
fibrils forming beta-pleated sheets. Culprit
proteins often originate from plasma.
• There are multiple types of amyloidosis, but all
amyloid stains with Congo Red dye, which
displays apple-green birefringence under
polarized light.
• Congo Red staining distinguishes amyloidosis
from other protein deposition diseases, in which
the pathogenic proteins don’t form fibrils.
Amyloidosis
• Grossly, involved organs may be enlarged and
have a “waxy” or “lardaceous” appearance when
cut. Organs may seem unusually firm or heavy.
See the small waxy deposits in
this cut kidney.
Note the distended appearance
of this liver.
Amyloidosis
See how glossy (waxy) this
cut liver looks.
Same liver. Arrows
point to small pale
deposits of waxy
material.
Early pathologists referred to
such organs as “lardaceous”,
because they looked as if they
were perfused with thick
grease.
Amyloidosis
• Histologically, amyloid looks amorphous
(“fluffy”) on H&E staining, but displays applegreen birefringence when stained with Congo
Red.
Amyloidosis
• Many different types of amyloidosis have
been characterized.
• They may occur by themselves (primary
amyloidosis)
• They may happen in conjunction with
another disease (secondary amyloidosis).
Amyloidosis - Table
Amyloidosis
Protein
Clinical Note
AL
Ig light chain
Can occur alone (primary
amyloidosis), may progress to a
plasma cell malignancy, or may
happen synchronously with a
plasma cell malignancy or dyscrasia
(e.g. Waldenström). Can also
happen in Hodgkin disease.
AH
Ig heavy chain
Associated with plasma cell
malignancy. Rare.
AA
Serum amyloid A (SAA)
Associated with chronic
inflammation or infection.
Dialysis
Β2 macroglobulin
Often affects shoulder joint in
longterm dialysis patients. Can
present with fracture.
Hereditary
Mutant transthyretin
Familial neuropathy and
cardiomyopathy syndromes
“Senile”
Wild-type transthyretin
Often cardiomyopathy
Organ-Specific
Most common is amyloid precursor
protein (APP) of Alzheimer disease.
Most common is Alzheimer
Clinical
• Amyloid may deposit in any one of a number of organs, with
differing results.
• Liver: hepatomegaly, elevated enzymes, loss of hepatic function
• Kidneys: enlarged kidneys, declining renal function, sometimes
proteinuria.
• Heart: Restrictive cardiomyopathy
• Brain: Amyloid angiopathy
• Peripheral Nerves: Neuropathy (muscle weakness, sensory loss)
• Skin: Thickening of skin
• Tongue: Macroglossia, dysphagia, dysarthria.
• Bones/Joints: Arthralgia, arthritis, pathologic fractures.
Treatment
• End-organ damage from amyloid is considered to be irreversible (although
patients may show some functional improvement during their treatment).
• In the case of AL amyloidosis with or without multiple myeloma, the
mainstay of treatment is chemotherapy with or without a bone marrow
transplant.
• If the primary disease process can be halted, then organ transplantation
may be an option.
• Otherwise, treatment is supportive.
– Dialysis and erythropoietin replacement for severe renal failure.
– Medications for congestive heart failure may include beta blockers, diuretics,
and angiotensin inhibitors.
– Pacemaker may be needed if conduction system problems result.
End of Story
• The patient is treated medically for his congestive heart
failure.
• The patient receives a pacemaker for his heart block.
• The patient goes on dialysis for his renal failure.
• Due to his malignancy, he is not an organ transplant
candidate.
• The patient is referred to a multiple myeloma specialist for
treatment, and is placed on a complex chemotherapy
regimen.
• Unfortunately, the patient’s prognosis is not good. Average
survival for AL amyloidosis plus multiple myeloma is 14
months. By contrast, mean survival with primary AL
amyloidosis is 32 months.