Grand Round For Pdf

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, nonnon-oscillating LV concentric hypertrophy, normal LV size, global LV hypokinesia Dilated LA, RA, RV LVEF 46% Moderate amount of pericardial effusion without tamponade sign Moderate to severe TR Increased E/A ratio (2.17)

DATA

Treatment and Course in Landseed Hospital Suspect LA thrombosis – Warfarin use (10/10~17), discontinued due to prolonged INR

Tumor markers CEA CA-125

0.5 299.3

ng/ml U/ml

(<3) (<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

74

73 HTN

71

HTN

Colon ca.

Unknown

69

72

67

43

41

CAD

Congestive heart failure

63

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 Rt ++ ++ ++ ++ Lt ++ ++ ++ ++

dor. pedis ++ ++

Laboratory Studies RBC

Hb

HCT

MCV

MCH

MCHC

Date

M/μL

g/dL

%

fL

pg

g/dL

Platele t 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

Date

mg/dl

mg/dl

mmol/l

mmol/l

mmol/l

mg/dl

2008/10/30

29.3

0.8

131

3.6

2.22

2.8

mmol/ L 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.

Date

*

mmHg

mmHg

2008/10/31

7.51

46.6

77.6

mmol/ L 37.1

mmol/ L 12.3

PT

PTT

INR

D-dimer

Date

sec

sec

U/L

μg/mL

2008/10/30

14

29.6

1.36

0.54

(<2.09)

(O2 N/C 3L/min)

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

*

*

*

2008/10/29

0-2

2-5

2-5

Hyaline (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 TP(g/dl) 5 1.6 RBC WBC Cell count <10,000 300 L : N : M + H = 56 : 36 : 8 Transudative pleural effusion Probably related to heart failure

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 TP(g/dl) 5 1.6 RBC WBC Cell count <10,000 300 L : N : M + H = 56 : 36 : 8 Transudative pleural effusion Probably related to heart failure

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

Congestive heart failure, NYHA class IV, cause to be determined Left atrial mass, suspectNegative thrombus pelvis CT Bilateral pleural effusion, pericardial Gynecological Consultation: no evidence of GYN disease effusion and ascites Favor elevated CA-125 due to Elevated CA-125 level effusions and ascites Hepatomegaly, cholestasis

Framingham Criteria for Congestive Heart Failure

Major criteria

Paroxysmal nocturnal dyspnea Neck vein distention Rales Radiographic cardiomegaly Acute pulmonary edema S3 gallop Increased central venous pressure Hepatojugular reflux Weight loss >4.5 kg in 5 days in response to treatment BNP

7062.66

pg/mL

Minor criteria Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by one third from maximum recorded Tachycardia 2 Major or 1 Major and 2 Minor

Depressed Ejection Fraction (<40%) Preserved Ejection Fraction (40-50%) Coronary artery disease Myocardial infarction Myocardial ischemia Chronic pressure overload Hypertension Obstructive valvular disease Chronic volume overload Regurgitant valvular disease Intracardiac (left-to-right) shunting Nonischemic dilated cardiomyopathy Familial / genetic disorders Toxic/drug-induced damage Metabolic disorder Viral Chagas' disease Disorders of rate and rhythm Chronic bradyarrhythmias Chronic tachyarrhythmias

Pathological hypertrophy Primary (hypertrophic cardiomyopathies) Secondary (hypertension) Aging Restrictive cardiomyopathy Infiltrative disorders (amyloidosis, sarcoidosis) Storage diseases (hemochromatosis) Fibrosis Endomyocardial disorders

Pulmonary Heart Disease Cor pulmonale Pulmonary vascular disorders

High-Output States Metabolic disorders Thyrotoxicosis Nutritional disorders (beriberi) 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 Nutritional disorders (beriberi) RIA:T3 126 ng/dL (80-200) Chronic tachyarrhythmias (0.2-3.2)Excessive blood-flow requirements RIA:TSH 11.3 IU/ml 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 Mild MR Aortic valve

Favor Restrictive Pattern Severe diastolic dysfunction – – – –

MV E max vel: 65.2 cm/sec MV A max vel: 24.3 cm/sec MV E/A: 2.7 (1-1.5) MV dec time: 140 ms (>220)

– Fibrocalcified degeneration,with limited opening – Ao root diam: 30 mm (17-33) – ACS: 14 mm (>15) – Ao V2 max: 67.1 cm/sec

Myocardial

Causes of Restrictive Cardiomyopathy

Noninfiltrative Idiopathic cardiomyopathy Familial cardiomyopathy Scleroderma Pseudoxanthoma elasticum Diabetic cardiomyopathy Infiltrative Amyloidosis Sarcoidosis Gaucher’s disease Hurler’s disease Fatty infiltration Storage diseases

Hemochromatosis Fabry’s disease Glycogen storage disease

Endomyocardial Endomyocardial fibrosis Hypereosinophilic syndrome Carcinoid heart disease Metastatic cancers Radiation Toxic effects of anthracycline Drugs causing fibrous endocarditis (serotonin, methysergide, ergotamine, mercurial agents, busulfan)

N Engl J Med. 1997 Jan 23;336(4):267-76

Hemodynamic Study Pressure (mmHg) RPAW MPA RV

33/19

30/19 CI

RA

CVP

SVC IVC

CO

PAWP

Mean (mmHg)

SaO2 (%)

22

99.9

24

1.13

L/min

45.8

23

0.8456.3 L/min/M2

19

19 61.2 mmHg

19 19

RFA

108/60SVRI

76

Ao

96/62

79

LV

80/20

22

(2.4-4)

mmHg(6-12)

542898.8 DSm2/cm5

(1600-2400)

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 – Moderately hypocellular marrow – M/E 3-5 / 1 – Mild plasmacytosis

Blast

4.5

Eos

5.0

Promyelo

6.5

Mono

1.0

Myelo

8.0

Lymph

31.5

Meta

5.0

Plasma

11.5

PMN

5.5

Proery / erythro

21.5

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 1.5 times of the But co-existing severe right 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 retention cardiac involvement

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

Urine Output

700 600

70 60

500

50

400

40

300

30

BUN

200

20

100 0

10

20

0 1 2 Creatinine

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

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

4

5

6

7

9

10

11

12

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

0

10000

1

2

Pleural Effusion Drainage

500

4

Dopamine

2

0

1

2

3

Furosemide 10mg IV BID Albumin

8

13

Furosemide 20mg PO BID Spironolactone 25mg PO BID

Furosemide 20mg PO QD

Ceftazidime

CVS consultation: not eligible for tx. due to advanced age and AL amyloidosis

Progressive dyspnea, ABG: poor PaO2, respiratory alkalosis and metabolic acidosis, on BiPAP, hesitate for DNR

1100

110

1000

100

SBP

900

90

800

80

Urine Output

700 600

70 60

500

50

400

40

300

30

BUN

200

20

100 0

10

20

0 1 2 Creatinine

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

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

4

5

6

7

9

10

11

12

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

0

10000

1

2

Pleural Effusion Drainage

500

4

Dopamine

2

0

1

2

3

Furosemide 10mg IV BID Albumin

8

13

Furosemide 20mg PO BID Spironolactone 25mg PO BID

Furosemide 20mg PO QD

Ceftazidime

CVS consultation: not eligible for tx. due to advanced age and AL amyloidosis

Found asystole at 6AM, CPCR for 45min, expired

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 HSCT

Patient not undergoing HSCT

Low risk (cardiac troponin < 0.035 mcg/L, NT-proBNP level < 332ng/L)

Not reached at 40 month

26.4 months

Intermediate risk (any 1 factor abnormal)

Not reached at 40 months

10.5 months

High risk(cardiac 8.4 months troponin > 0.035 mcg/L, NT-proBNP level > 332ng/L)

3.5 months

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!