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Grand Round

February 17, 2009
R2 曾昱超 / R4 黃慶昌 / VS 張博淵
Case Presentation
A 66-year-old woman with progressive
dyspnea for 10 months
Brief History
Personal history
– Occupation: housewife
– Denied other systemic disease, HTN(-), DM(-)
HBV(-), HCV(-)
– Surgical history: nil
– Smoking: 1-2 PPD for 30 years, quitted for
months
– Alcohol: nil
– No known drug allergy
Brief History
Shortness of breath for 10 months
– Exertional dyspnea
– Accompanied with chest pain and palpitation
sometimes
– Denied paroxysmal nocturnal dyspnea
Bilateral lower leg pitting edema developed later
At Landseed Hospital
– Dx as congestive heart failure
– Hospitalized for 4 times
– Improved symptoms after discharge
Brief History
Progressive dyspnea two days before
hospitalization at Landseed hospital
Orthopnea
Paroxysmal nocturnal dyspnea
Chest tightness
– Persistent
– Mid-chest
– No radiation
Decreased urine output
Brief History
Dry cough
Poor appetite, general weakness in recent
two weeks
Abdominal distension in one month
Body weight loss of 9kg (50kg41kg) in 6
months
Right eyelid ecchymosis
Denied fever, sputum, increased water
intake
Treatment and Course in
Landseed Hospital
Hospitalized at Landseed hospital on
2008/10/5
Water restriction and diuretic
Nitrates
ACEI
Aspirin
Symptoms improved mildly
Echocardiography (10/8)

D-dimer 2393.24 ng/ml (<500)
LA mass, non-
non-oscillating
LV concentric hypertrophy, normal LV size, global LV hypokinesia
Dilated LA, RA, RV
LVEF 46%
Moderate amount of pericardial effusion without tamponade sign DATA
Moderate to severe TR
Increased E/A ratio (2.17)
Treatment and Course in
Landseed Hospital
Suspect LA thrombosis
– Warfarin use (10/10~17), discontinued due to
prolonged INR
Tumor markers
CEA 0.5 ng/ml (<3)
CA-125 299.3 U/ml (<35)
Abdominal / Pelvis CT (10/24)
Treatment and Course in
Landseed Hospital
Hypotension (SBP around 80-100mmHg)
during whole course of hospitalization
Refer to NTUH on 10/29 for further
treatment of heart failure
Family History**
76 72

Pneumonia Unknown

74 73 71 69 72 67 63

HTN HTN Colon ca. CAD

Congestive heart failure
43 41
Physical Examination
General appearance: chronic ill looking
Consciousness: clear and oriented
Vital sign
BP 97/70mmHg
BT 37°C PR 92 bpm RR 18 per minute
SpO2 100% under N/C 3L/min
HEENT
Conjunctiva: not pale Sclera: anicteric
Pupil: isocoric LR(+/+)
Bilateral upper eyelid purplish papules
Throat: not injected, no oral ulcer
Macroglossia(+)
Physical Examination
Neck
Supple, no lymphadenopathy, no goiter
Jugular vein engorgement
Hepatojugular reflux
No Kussmaul’s sign
No carotid bruit
Chest
Symmetric expansion
Decreased BS at bilateral dependent part
Bilateral diffuse crackles, no wheezing
Physical Examination
Heart
PMI: at 5th ICS along LMCL
Regular heart beat
Distant heart sound, no audible friction rub
Gr. II/VI pansystolic murmur over LLSB, no radiation
No heave, no thrill, no S3 gallop, no tumor plop
Abdomen
Distended abdomen, no rebound tenderness
Shifting dullness
Bowel sound: normoactive
Liver: 10cm below right subcostal margin along
RMCL
Spleen: impalpable
Physical Examination
Extremity
Bilateral lower leg pitting edema
No cyanosis
Peripheral Pulse
Rad. Brach. Femoral P. Tibial dor. pedis
Rt ++ ++ ++ ++ ++
Lt ++ ++ ++ ++ ++
Laboratory Studies
Platele
RBC Hb HCT MCV MCH MCHC
t
Date M/μL g/dL % fL pg g/dL K/μL

2008/10/29 4.7 15.5 47 100 33 33 226

WBC Seg. Band Lym. Mono. Eos. Baso.

Date K/μL % % % % % %

2008/10/29 6.18 75 0 18.9 5.5 0.3 0.3

Pro. Myelo. Meta

Date % % %

2008/10/29 0 0 0
Laboratory Studies
UN CRE Na K Ca P Mg
mmol/
Date mg/dl mg/dl mmol/l mmol/l mmol/l mg/dl
L
2008/10/30 29.3 0.8 131 3.6 2.22 2.8 0.62

ALB GLO AST ALT T-BIL D-BIL LDH

Date g/dL g/dL U/l U/l mg/dL mg/dL U/l

2008/10/30 3.23 1.77 23 24 1.83 0.9 604

ALP GT UA CK CKMB Tn I

Date U/L U/L mg/dL U/L U/L ng/ml

2008/10/30 310 162 10.8 40 11.2 0.26
Laboratory Studies
TG T-CHO HDL-C LDL-C HbA1c

Date mg/dL mg/dL mg/dL mg/dL %

2008/10/31 91 194 38 138 6.1

PH pCO2 pO2 HCO3 B.E.
mmol/ mmol/
Date * mmHg mmHg
L L
2008/10/31 7.51 46.6 77.6 37.1 12.3 (O2 N/C 3L/min)

PT PTT INR D-dimer

Date sec sec U/L μg/mL

2008/10/30 14 29.6 1.36 0.54 (<2.09)
Laboratory Studies
Sp. Gr pH(C) Protein Glu.(C) Ket. O.B.(C) Urobil.

Date * * * * * * EU/dL

2008/10/29 1.011 5.5 - - - - Normal

RBC(S) WBC(S) Epi (S) Cast(S) Cry(S) Other Bact.

Date /HPF /HPF /HPF /LPF * * *
Hyaline
2008/10/29 0-2 2-5 2-5 - - -
(2-4)
2008/10/29
2008/11/3
Electrocardiogram
Tentative Diagnosis
Congestive heart failure, NYHA class IV,
cause to be determined
Left atrial mass, suspect thrombus
Bilateral pleural effusion, pericardial
effusion and ascites
Elevated CA-125 level
Hepatomegaly, cholestasis
Tentative Diagnosis
Clear yellowish
Serum Pleural effusion
LDH(U/L) 604 193
Congestive heart failure, NYHA class IV,
TP(g/dl) 5
RBC
1.6
WBC
cause to be determined
Cell count <10,000 300
L : N : M + H = 56 : 36 : 8
Transudative pleural effusion
Left atrial mass, suspect thrombus
Probably related to heart failure

Bilateral pleural effusion, pericardial
effusion and ascites
Elevated CA-125 level
Hepatomegaly, cholestasis
Tentative Diagnosis
Clear yellowish
Serum Pleural effusion
LDH(U/L) 604 193
Congestive heart failure, NYHA class IV,
TP(g/dl) 5
RBC
1.6
WBC
cause to be determined
Cell count <10,000 300
L : N : M + H = 56 : 36 : 8
Transudative pleural effusion
Left atrial mass, suspectNegative
thrombus
Probably related to heart failure
pelvis CT
Bilateral pleural effusion, pericardial
Gynecological Consultation: no
effusion and ascites evidence of GYN disease
Favor elevated CA-125 due to
Elevated CA-125 level effusions and ascites
Hepatomegaly, cholestasis
Tentative Diagnosis
Clear yellowish
Serum Pleural effusion
LDH(U/L) 604 193
Congestive heart failure, NYHA class IV,
TP(g/dl) 5
RBC
1.6
WBC
cause to be determined
Cell count <10,000 300
L : N : M + H = 56 : 36 : 8
Transudative pleural effusion
Left atrial mass, suspectNegative
thrombus
Probably related to heart failure
pelvis CT
HBV(-), HCV(-)
Bilateral pleural effusion, pericardial
No definite mass lesion in abdominal CT
Gynecological Consultation: no
Elevated ALP and -GT level
effusion and ascites
Dilated IVC
evidence of GYN disease
Favor elevated CA-125 due to
Elevated CA-125 level effusions and ascites
Co-existing heart failure
Favor congestive liver

Hepatomegaly, cholestasis
Framingham Criteria for Congestive
Heart Failure
Major criteria Minor criteria
Paroxysmal nocturnal Bilateral ankle edema
dyspnea
Nocturnal cough
Neck vein distention
Rales Dyspnea on ordinary
exertion
Radiographic cardiomegaly
Acute pulmonary edema Hepatomegaly
S3 gallop Pleural effusion
Increased central venous Decrease in vital capacity by
pressure one third from maximum
Hepatojugular reflux recorded
Weight loss >4.5 kg in 5 days Tachycardia
in response to treatment
2 Major
or
BNP 7062.66 pg/mL
1 Major and 2 Minor
Depressed Ejection Fraction (<40%) Preserved Ejection Fraction (40-50%)
Coronary artery disease Pathological hypertrophy
Myocardial infarction Primary (hypertrophic cardiomyopathies)
Myocardial ischemia Secondary (hypertension)
Chronic pressure overload Aging
Hypertension Restrictive cardiomyopathy
Obstructive valvular disease Infiltrative disorders (amyloidosis,
Chronic volume overload sarcoidosis)
Regurgitant valvular disease Storage diseases (hemochromatosis)
Intracardiac (left-to-right) shunting Fibrosis
Nonischemic dilated cardiomyopathy Endomyocardial disorders
Familial / genetic disorders Pulmonary Heart Disease
Toxic/drug-induced damage Cor pulmonale
Metabolic disorder Pulmonary vascular disorders
Viral High-Output States
Chagas' disease Metabolic disorders
Disorders of rate and rhythm Thyrotoxicosis
Chronic bradyarrhythmias Nutritional disorders (beriberi)
Chronic tachyarrhythmias Excessive blood-flow requirements
Systemic arteriovenous shunting
Chronic anemia

Harrison's Principles of Internal Medicine, 17th Edition
Depressed Ejection Fraction (<40%) Preserved Ejection Fraction (40-50%)
Coronary artery disease Pathological hypertrophy
Myocardial infarction Primary (hypertrophic cardiomyopathies)
Myocardial ischemia Secondary (hypertension)
Chronic pressure overload Aging
Hypertension Restrictive cardiomyopathy
Obstructive valvular disease Infiltrative disorders (amyloidosis,
Chronic volume overload sarcoidosis)
Regurgitant valvular disease Storage diseases (hemochromatosis)
Intracardiac (left-to-right) shunting Fibrosis
Nonischemic dilated cardiomyopathy Endomyocardial disorders
Familial / genetic disorders Pulmonary Heart Disease
Toxic/drug-induced damage Cor pulmonale
Metabolic disorder Pulmonary vascular disorders
Viral High-Output States
Chagas' disease Metabolic disorders
Disorders of rate and rhythm Thyrotoxicosis
Chronic bradyarrhythmias
RIA:T3 126 ng/dL (80-200) Nutritional disorders (beriberi)
Chronic tachyarrhythmias
RIA:TSH 11.3 IU/ml (0.2-3.2)Excessive blood-flow requirements
RIA:Free T4 1.56 ng/dL (0.89-1.79) Systemic arteriovenous shunting
Favor subclinical hypothyroidism Chronic anemia

Harrison's Principles of Internal Medicine, 17th Edition
Dilated LA and right heart
– LA dimension: 50 mm (20-35)
– RVDd: 26 mm (5-21)
No LA mass or thrombus
Concentric LVH
– IVSd: 13 mm (7-10)
– LVPWd: 15 mm (7-10)
Sparkling myocardium
Global hypokinesia
Normal LV size
– LVIDd: 3.2 cm (42-60)
– LVIDs: 2.7 cm (22-43)
Impaired LV contractility
– FS: 15.6 % (25-42)
– EF(M-mode): 34.0 %
– EF(area-length): 38.9 %
Moderate amount of pericardial
effusion without RA/RV
collapse sign
Borderline pulmonary
hypertension
– PA acc time: 90 ms
– PA V2 max: 45.9
cm/sec
– TR max vel: 239.0
cm/sec (<250)
– TR max PG: 22.8
mmHg
Tricuspid regurgitation,
moderate to severe
Favor Restrictive Pattern
Mild MR
Aortic valve
– Fibrocalcified
degeneration,with
Severe diastolic dysfunction limited opening
– MV E max vel: 65.2 cm/sec – Ao root diam: 30 mm
– MV A max vel: 24.3 cm/sec (17-33)
– MV E/A: 2.7 (1-1.5) – ACS: 14 mm (>15)
– MV dec time: 140 ms (>220) – Ao V2 max: 67.1
cm/sec
Causes of Restrictive
Cardiomyopathy
Myocardial Hemochromatosis
Noninfiltrative Fabry’s disease
Idiopathic cardiomyopathy Glycogen storage disease
Familial cardiomyopathy Endomyocardial
Scleroderma Endomyocardial fibrosis
Pseudoxanthoma elasticum Hypereosinophilic syndrome
Diabetic cardiomyopathy Carcinoid heart disease
Infiltrative Metastatic cancers
Amyloidosis Radiation
Sarcoidosis Toxic effects of anthracycline
Gaucher’s disease Drugs causing fibrous endocarditis
Hurler’s disease (serotonin, methysergide, ergotamine,
Fatty infiltration mercurial agents, busulfan)
Storage diseases

N Engl J Med. 1997 Jan 23;336(4):267-76
Hemodynamic Study
Pressure Mean SaO2
(mmHg) (mmHg) (%)
RPAW 22 99.9
CO 1.13 L/min
MPA 33/19 24 45.8
RV 30/19 CI 23 0.8456.3
L/min/M2 (2.4-4)
RA CVP 19 19 61.2
mmHg
SVC 19
PAWP 22 mmHg(6-12)
IVC 19
RFA 108/60SVRI 76 DSm2/cm5
542898.8 (1600-2400)
Ao 96/62 79
LV 80/20
Coronary Angiography
Non-significant coronary artery narrowing
Endomyocardial
biopsy
H&E 40X
Endomyocardial
biopsy
H&E 100X
Interstitial Fibrosis

Congo red 40X,
polarized light
Dermatologist Consultation

Favor skin involvement of amyloidosis
Mild eosinophilic
amorphous material in the
interstitia of subcutis

H&E 40X
Mild eosinophilic
amorphous material in the
interstitia of subcutis

H&E 100X
Eosinophilic, amorphous,
fissured material in the
dermis

H&E 40X
Eosinophilic, amorphous,
fissured material in the
dermis

H&E 100X
Congo red 40X
Congo red 40X,
polarized light
Amyloidosis

Congo red 40X,
polarized light
N Engl J Med 2003;349:583-96.
Circulation 2005;112;2047-2060
Urine IFE
Albumin and all fractions globulins, but
no Bence Jones protein
Kappa free light chain 13.7 mg/L
(1.35-24.19)
Lambda free light chain 9.7 mg/L
(0.24-6.66)
Free kappa/lambda ratio 1.4 (2.04-10.37)

Circulation 2005;112;2047-2060
Urine IFE
Albumin and all fractions globulins, but
Serum IFE
no Bence Jones protein
A thin band of monoclonal lambda chain
Kappa free light chain 13.7 mg/L
Kappa free light chain 7.8 mg/L
(1.35-24.19)
(3.30-19.4)
Lambda free light chain 9.7 mg/L
Lambda free light chain 936.0 mg/L
(0.24-6.66)
(5.71-26.30)
Free kappa/lambda ratio 1.4 (2.04-10.37)
Free kappa/lambda ratio 0.01 (0.26-1.65)

Circulation 2005;112;2047-2060
Bone Marrow Study
Aspiration Blast 4.5 Eos 5.0
– Moderately
Promyelo 6.5 Mono 1.0
hypocellular marrow
– M/E 3-5 / 1 Myelo 8.0 Lymph 31.5

– Mild plasmacytosis Meta 5.0 Plasma 11.5

PMN 5.5 Proery / 21.5
erythro
Hypocellular Marrow

H&E 40X
Hypocellular Marrow
H&E 100X
N Engl J Med 2003;349:583-96.
AL Amyloidosis and Kidney
Renal biopsy evidence of amyloid deposits
Biopsy proof of amyloid at an alternate site
24-hr urine protein excretion > 0.5 g/day
Exclude other cause of proteinuria

24-hr urine protein 0.12g/day

American Journal of Hematology 79:319 - 328 (2005)
AL Amyloidosis and Liver
Liver biopsy proof and evidence of organ
dysfunction
Amyloid diagnosed at another site
Hepatomegaly, total liver span greater
than 15 cm or
Alkaline phosphatase 1.5 times of the
upper limit

American Journal of Hematology 79:319 - 328 (2005)
AL Amyloidosis and Liver
Liver biopsy proof and evidence of organ
dysfunction
Amyloid diagnosed at another site
Hepatomegaly, total liver span greater
Liver Span measured on CT: 13.8 cm
than 15 cm or
ALP 310 U/L (220)
Alkaline phosphatase
But co-existing 1.5 times
severe right of the
heart failure!
upper
So?? limit

American Journal of Hematology 79:319 - 328 (2005)
Amyloidosis and Pleural Effusion
Transudative pleural effusion also
occurred with pleural involvement
Not only related to restrictive
cardiomyopathy
Ascites?? Pericardial effusion??

No pleural biopsy result

Current Opinion in Pulmonary Medicine 2005, 11:324-328
Journal of Gastroenterology and Hepatology (2005) 20, 325–329
Survey for Other Organ /
System Involvement
Nervous system
GI tract
Lung
Soft tissue

American Journal of Hematology 79:319 - 328 (2005)
Final Diagnosis
Systemic AL amyloidosis with soft-tissue
and cardiac involvement
Hepatomegaly, probably congestive liver
or amyloidosis related
Pleural effusion, ascites, and pericardial
effusion, probably heart failure, or
amyloidosis related
Treatment
High-dose chemotherapy followed by
autologous stem cell transplantation
– 2 or fewer organs involved,
– absence of severe cardiac involvement,
– creatinine < 2 mg/dL
– age 65 years or younger
– Normal respiratory function tests
High peritreatment mortality in patients with
cardiac involvement
Oral melphalan and high dose dexamethasone
N Engl J Med 2007;357:1083-93.
Ann Intern Med, Jan 2004; 140: 85 - 93.
Treatment
High-dose chemotherapy followed by
autologous stem cell transplantation
– 2 or fewer organs involved,
– absence of severe cardiac involvement,
– creatinine < 2 mg/dL
– age 65 years or younger
– Normal respiratory function tests
Not applied due to
High peritreatment mortalityprogressive
in patients
fluid with
cardiac involvement retention
Oral melphalan and high dose dexamethasone
N Engl J Med 2007;357:1083-93.
Ann Intern Med, Jan 2004; 140: 85 - 93.
1100 110

1000 100
SBP
900 90

800 80

700 Urine 70

600 Output 60

500 50

400 40

300 30

200 BUN 20

100 10

0 0
20
Creatinine
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

0
10000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Pleural
500 Effusion
Drainage

4

2
Dopamine

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Furosemide 20mg PO BID Furosemide 20mg
Furosemide
10mg IV BID Spironolactone 25mg PO BID PO QD

Albumin Ceftazidime

CVS consultation: not Progressive dyspnea,
eligible for tx. due to ABG: poor PaO2,
advanced age and AL respiratory alkalosis and
amyloidosis metabolic acidosis,
on BiPAP, hesitate for DNR
1100 110

1000 100
SBP
900 90

800 80

700 Urine 70

600 Output 60

500 50

400 40

300 30

200 BUN 20

100 10

0 0
20
Creatinine
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

0
10000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Pleural
500 Effusion
Drainage

4

2
Dopamine

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Furosemide 20mg PO BID Furosemide 20mg
Furosemide
10mg IV BID Spironolactone 25mg PO BID PO QD

Albumin Ceftazidime

CVS consultation: not Found asystole at
eligible for tx. due to 6AM, CPCR for 45min,
advanced age and AL expired
amyloidosis
Discussion
Amyloidosis
Extracellular deposition of pathologic
insoluble fibrillar proteins in organs and
tissues
Stain with Congo red, appearing red
microscopically in normal light but apple
green when viewed in polarized light

New England Journal of Medicine. 337(13):898-909, 1997
AL Amyloidosis
Associated with a plasma cell dyscrasia
Estimated 2000 to 2500 new cases
annually in the United States
The presence of cardiac amyloidosis is
frequently the worst prognostic factor
Once congestive heart failure occurs, the
median survival is 6 months in untreated
patients
N Engl J Med 2003;349:583-96.
Circulation 2005;112;2047-2060
Cardiac Manifestation
Predominance of right heart failure
Low BP
Chest discomfort
a small but persistent elevation in serum
troponin may be present
Low voltage on the ECG
Atrial arrhythmias associated with a very
high incidence of thromboembolism
Circulation 2005;112;2047-2060
J Am Coll Cardiol 2007;50:2101–10
Echocardiographic Features
Nondilated ventricles with
concentric left ventricular
thickening
Right ventricular thickening
Prominent valves,
Infiltration of the atrial septum
“granular sparkling” myocardial
EF normal or nearly normal
until late in the disease
Restrictive pattern by doppler
echocardiography

Circulation 2005;112;2047-2060
J Am Coll Cardiol 2007;50:2101–10
Echocardiographic Features
Decreased ratio of voltage to left
ventricular mass
 suggests an infiltrative cardiomyopathy,
of which amyloidosis is the commonest
cause

Circulation 2005;112;2047-2060
J Am Coll Cardiol 2007;50:2101–10
Circulation 2005;112;2047-2060
Diagnosis of AL Amyloidosis
Tissue prove
Demonstration of monoclonal light chain
SPEP, UPEP
IFE
Free light chain assay
Kappa / lambda ratio
Bone marrow study to exclude other diseases
associated with plasma cell dyscrasia
New England Journal of Medicine. 337(13):898-909, 1997
Risk Stratification Model to Predict
Progression of Primary Amyloidosis
Risk Group Patient undergoing Patient not
HSCT undergoing HSCT
Low risk (cardiac Not reached at 40 26.4 months
troponin < 0.035 mcg/L, month
NT-proBNP level <
332ng/L)
Intermediate risk (any Not reached at 40 10.5 months
1 factor abnormal) months

High risk(cardiac 8.4 months 3.5 months
troponin > 0.035 mcg/L,
NT-proBNP level >
332ng/L)
Mayo Clinic Proceedings. 81(5):693-703, 2006 May
Management
Intravenous melphalan and HSCT with a
complete hematologic response in 40% of
patients
Advanced heart disease: risk of
peritreatment mortality as high as 30%
Heart transplant?

Ann Intern Med. 2004;140:85–93
Bone Marrow Transplant. 1999;24:853-855
Heart 2001;85:202–207
Heart Transplant?
Donor shortage
Recurrence in graft
Unfavorable survival result compared to
other group
Should be offered as last resort

J Heart Lung Transplant 2005;24:1763-5
Heart Transplant?
Sequential heart and autologous stem cell
transplantation for systemic AL
amyloidosis
– Heart transplantation followed by SCT was
performed in 5 patients with AL amyloidosis
and predominant cardiomyopathy.
– 3 of the 5 did not have evidence of cardiac or
extracardiac amyloid accumulation

Blood 2006 107: 1227-1229
Take Home Message
Decreased ratio of voltage to left
ventricular mass should raise the
suspicion of cardiac amyloidosis
AL amyloidosis with cardiac involvement
implicates poor prognosis
Sequential heart and HSCT may be
considered in selected patient with AL
amyloidosis
Thank You for Your Attention!