< Brief history
>
A 61-year-old male patient was admitted
due to progressive dyspnea on exertion for 2 months.
One year before the
admission, this patient found ecchymosis at the peri-orbital and mouth angle.
In addition, he felt fatigue and shortness
of breath on exertion. Chest roentgenogram at local
clinics revealed a moderate to large amount of pleural
effusion bilaterally. He had undergone a thoracentesis to
yield transudative effusion. He was referred to a cardiovascular
specialist in a medical center with a tentative diagnosis of
congestive heart failure. Echocardiography revealed good
left ventricular systolic function (ejection fraction,
66%), moderated mitral regurgitation, moderated aortic
regurgitation, and left ventricular diastolic dysfunction.
Coronary angiogram revealed patent coronary arteries. His
symptoms improved after treatment with diurestics. He was discharged 2
weeks later with furosemide(Lasix).
However, his symptoms
became worse after discharge. He took some Chinese herb medicine, without
improvement. Two months later, because of the intractable symptoms, he
was brought to our hospital. On physical examination, the blood
pressure was 131/80 mmHg, the temperature was 36.2℃,
the pulse was 125 beats per minute and the respirations
were 20 breaths per minute. The conjunctiva was pink and
the sclera was anicteric. Oral cavity revealed macroglossia
(figure
1 ). There was no jugular vein engorgement
or lymphadenopathy. The chest inspection was normal and expansion
was symmetric in palpation. Increasing dullness was
noted at bilateral lower lungs by percussion. The
auscultation showed decrease of breath sounds at bilateral lower
lobes and bi-basilar rales without wheezes or crackles.
The heart sounds were regular with grade II/VI systolic
murmurs at the apex. No friction rub was noted. The
abdomen was prominently distended and nontender. The bowel
sounds were normoactive. The edge of the liver descended at
least 5 cm below the right costal margin and crossed the
midline by 3 cm. The spleen was impalpable. No shift dullness
was noted. The extremities were freely movable without edema
or cyanosis. Several purpura lesions were noted on his
eyelids, face and neck (figure
2). On neurological
examination, the cranial-nerve functions were intact. Motor
power was 5/5 in his arms and leg with normal muscle tone and
tendon reflex. Sphincter was intact.
Chest roentgenogram performed revealed
a moderate to large amount of pleural effusion
bilaterally (figure
3
). A repeat thoracentesis showed transudative
effusion. In electrocardiogram (figure
4), broad P wave was noted in
lead II and a prominent negative vector of P wave was also
noted in V1. Left deviation of QRS axis was also identified.
Besides, T wave inversion was noted in V4-6, lead I and aVL.
After admission, echocardiography
revealed borderline left ventricle contractility (ejection
fraction, 52%), mild mitral, and aortic regurgitation. In
Doppler analysis of mitral flow, it characterized as
a restrictive pattern without respiratory
variation. Restrictive cardiomyopathy (RCM) with congestive heart
failure was highly suspected. Cardiac catheterization 2 days later
confirmed the diagnosis of RCM.
Serum protein and
immunofixation electrophoresis revealed IgG/κλ bi-clonal gammopathy
which leaded to the diagnosis of AL amyloidosis. To confirm the
diagnosis, tissue biopsies of his right ventricular
endomyocardium, skin, bone marrow, rectum, gingival and
abdominal subcutaneous fat were performed, but all were
negative for amyloid deposition.
During the hospitalization, his
symptoms progressed with intractable pleural effusion
accumulation. The renal function was also deteriorating.
Cardiac transplantation for this patient was advised after the
cardiovascular surgeon consultation. He underwent heart
transplantation 3 weeks later. The specimen from the failing
heart confirmed the diagnosis of amyloidosis pathologically.
The post-operative course was smooth and was discharged one
month after operation.
< Lab Data
>
CBC/DC:
WBC K/μL |
Hb g/dL |
Hct % |
MCV fL |
Plt k/μL |
Seg % |
Eos % |
Baso % |
Mon % |
Lym % |
5.6 |
14.8 |
42.6 |
85.7 |
242 |
48.2 |
2.0 |
0.2 |
5.9 |
48.4 |
Biochemistry/Electrolyte:
Bil-T mg/dL |
Bil-D mg/Dl |
AST U/L |
ALT U/L |
ALP U/I |
BUN mg/dL |
Cr mg/dL |
Alb g/dL |
TP g/dL |
0.67 |
0.26 |
35 |
33 |
389 |
13.5 |
1.0 |
* |
6.3* |
LDH U/L |
CK U/L |
CK-MB U/L |
Tn-I ng/ml |
Na mmol/L |
K mmol/L |
Ca mmol/L |
Glu mg/dL |
349 |
88 |
8.5 |
0.118 |
135 |
4.2 |
2.12 |
95 |
TSH |
3.45 |
Ref. 0.1 ~ 4.5 (μIU/mL) |
FT4 |
1.03 |
Ref. 0.6 ~ 1.75
(ng/dL) |
Bone Marrow Aspiration:
Hematological Diagnosis of BM:
Plasmacytosis, mild
Serology/Blood:
IgA |
82.2 |
Ref. 259.34 ± 82.84 (mg/dl) |
IgG |
1010.0 |
Ref. 1419.63 ± 279.84 (mg/dl) |
IgM |
61.4 |
Ref. 160.57 ± 72.2
(mg/dl) |
CEA |
0.87 |
Ref. <3.0 (ng/ml) |
AFP |
2.95 |
Ref. <20 (ng/ml) |
Serolgies: negative for S.T.S, Anti-HIV, HBsAg, HBeAg,
IgM-Anti-HAV, Anti-hepatitis C Virus, CMV Ab, HSV Ab, VZV Ab,
Toxoplasma IgG Ab, EBV-VCA IgG Antibody
Acid-fast smear of pleural effusion, negative
Culture of pleural effusion, negative for bacteria, fungi,
mycobacteria
PT/PTT:
PT Sec |
PT cont sec
|
PTT sec |
PTT cont sec
|
INR |
11.4 |
11.9 |
38.5 |
35.5 |
1.0 |
11.6 |
11.8 |
25.8 |
29.6 |
1.1 |
Peripheral blood smear: WBC and Platelet are adequate,
no Rouleaux formation of RBC
Serum electrophoresis: Low albumin and increased alpha
1 & alpha 2 globulins
Serum immunofixation electrophoresis (IFE) Two bands of
IgG/lambda gammopathy
Pleural Effusion:
Appearance |
Sp. Gr. |
Rivalta's |
WBC |
RBC |
Sediment L:N:M |
Glu AC mg/dL |
TP g/dL |
LDH U/L |
Y, C |
1.013 |
- |
500 |
<10000 |
59:15:26 |
120 |
1.5 |
103 |
Urinalysis:
Outlook |
Sp.Gr |
PH |
Pro |
Sugar |
Ket |
OB |
Uro |
Bil |
WBC |
RBC |
Epi |
Crys |
Cast |
Y, C |
1.01 |
6.5 |
- |
- |
- |
- |
0.1 |
- |
0-1 |
0-1 |
0-1 |
- |
- |
Urine IFE:
Quant. of Kappa |
316 |
Ref. 598 ~ 1329 (mg/dl) |
Quant. of Lamda |
450 |
Ref. 280 ~ 665 (mg/dl) |
24 hr. Urine: 24hr protein loss = 0.588g/day
Pleural Effusion Cytology: All negative for malignant
cells
Pathology: Endomyocardial biopsy
- Myocardial hypertrophy with enlarged and
hyperchromatic nuclei.
- Some fibrin and leukocytes are
seen covered on the surface. Mild increase in interstitial
cellularity is also present.
- No evidence of amyloidosis is seen under H&E and
Congo-red stains.
Bone marrow Hypocellularity with hemopoietic components
accounting for about 20 % of the marrow spaces
Skin Biopsy Hemorrhage and red blood cell
extravasation, no amyloid deposition at perivascular area is
found by congo red stain.
Gingiva Punch Biopsy No evident amyloid deposition can
be found in H & E and Congo red stains.
Endoscopic Biopsy Chronic colitis, focal fatty
infiltration in lamina propria.
Subcutaneous fat
- There is no eosinophilic deposition
around vessels and nerves
- Congo red stain is also negative under polarized
light
Heart Specimen after orthotopic
transplantation
- Variable hypertrophy and
degeneration of the myocardial fiber with vacuolar
degeneration and focal interstitial fibrosis.
- The endocardium is thickened.
- The aortic valve, pulmonary valve,
mitral valve, and tricuspid valve reveal myxomatous
degeneration.
- Mild to moderate atherosclerosis is
found in the coronary arteries (LAD, LCX, and RCA).
- In the pericardial fat tissue and
epicardium, amorphous hyalinized materials are noted around
small arteries, fat lobules (adjacent myocardium, and in the
nerve fibers).
- Under Congo-red stain and polar microscopic
examination, there amorphous hyalinized materials reveal
apple-green birefrigence. Therefore, amyloidosis is
considered.
<
Discussion >
Restrictive
cardiomyopathy (RCM) refers to a group of disorders in which
the heart chambers are unable to fill with blood properly
because of stiffness of the heart. Restrictive cardiomyopathy
is often caused by diseases in other parts of the body. One
known cause is cardiac amyloidosis. In
restrictive cardiomyopathy, the heart is normal in size or
only slightly enlarged, but it cannot relax normally during
diastole. Later in the disease, the
heart may not pump blood
efficiently.
Cardiac
amyloidosis is a disorder caused by deposits of an abnormal
protein (amyloid) in the heart tissue, resulting in decreased
heart function. Fibrils are proteins produced in excess that
are deposited in different organs and slowly replace normal
tissue. Cardiac amyloidosis is classified by the protein
precursor as primary, secondary (reactive), senile systemic,
hereditary, isolated atrial, and hemodialysis-associated
amyloidosis. Cardiac amyloidosis usually occurs during primary
amyloidosis. Primary amyloidosis usually accompanies multiple
myeloma, a blood disorder in which too much of a certain type
of protein is produced. Primary amyloidosis is rare, with an
incidence of 8.9 per million population. It affects
more men than women (3:2), usually
around the sixth decade of
life.
The typical
picture of cardiac amyloidosis is that of a rapidly
progressive congestive heart failure (CHF) due to restrictive
cardiomyopathy, but systolic dysfunction occurs later in the
course of the disease. Dilated cardiomyopathy is seen in only
5% of the patients and occasionally cardiac amyloidosis may
masquerade as hypertrophic cardiomyopathy. Sudden cardiac
death accounts for 30% to 50% of all cardiac deaths in
systemic amyloidosis and may be due to ventricular
arrhythmias, atrioventricular block, or acute
electromechanical dissociation. Atrial fibrillation is found
in 10-20% of cardiac amyloidosis, due to atrial enlargement,
atrial infiltration or congestive heart failure. Atrial thrombi are described even in sinus
rhythm related to an impairment of
atrial emptying or deranged clotting
factors.
The diagnosis
of cardiac amyloidosis is difficult to make. The findings from
physical examination are not specific and may indicate cardiac
enlargement heart and pulmonary or systemic congestion.
Auscultations may reveal lung crackles, heart murmurs, or
other abnormal sounds. The liver may be enlarged and neck
veins may be distended. The blood pressure may be
low or may drop when rising
to a standing position (orthostatic
hypotension).
Electrocardiogram may reveal
conduction disturbances, arrhythmias such as atrial
fibrillation, ventricular tachycardia, or premature and
ectopic beats. Low voltage in the limb leads on
electrocardiogram in the presence of increased left ventricle
mass is highly suggestive of cardiac amyloidosis.
Echocardiogram is a very important
tool for the diagnosis of amyloidosis. Typically, increased
thickness of left ventricular walls and a granular sparkling
appearance of myocardium are seen. Transmitral and pulmonary
venous Doppler findings may reveal the nature of impaired
relaxation (restrictive pattern). Tissue Doppler imaging,
strain rate imaging, and ultrasonic tissue characterization
may be useful in the early diagnosis of cardiac
amyloidosis.
If cardiac amyloidosis is
suspected, serum and urine protein and immunofixation
electrophoresis are the next diagnostic steps. The presence of
abnormal light chain suggests the diagnosis of primary
amyloidosis. A negative immunofixation test alone will not
rule out amyloidosis, as it can occur in non-secretory
amyloidosis or in other forms of amyloidosis (familial or
senile amyloidosis).
The confirmation of amyloidosis
requires some tissue biopsy (fat pad aspirate or other
tissues). A bone marrow biopsy is required to characterize the
monoclonal gammapathy and usually more than 5% plasma cells
are found in primary amyloidosis. Endomyocardial biopsy is
sensitive, and is always required in isolated cardiac
involvement.
The prognosis
of cardiac amyloidosis is poor, with a median survival of one
to two years. The major cardiac prognostic factors are heart
failure syptoms, LV ejection fraction less than 50% and
ventricular septal thickness more than 15 mm. Recently, brain
natriuretic peptide have been utilized as a good serum marker.
A N-terminal pro-BNP level of 152 pmol/L indicates heart
involvement, and is a marker of myocardial dysfunction and of
heart toxicity caused by amyloidogenic light chains. Cardiac troponins
(I and T) are modestly elevated
in patients with advanced cardiac
amyloidosis.
Management of
cardiac failure in patients with amyloidosis is difficult.
Usually larger doses of diuretics are required careful
monitoring. Digitalis should only be used in selected patients
in atrial fibrillation to control heart rate.
Angiotensin-converting enzyme inhibitors should be used
cautiously because of orthostatic hypotension and associated
renal disease. Calcium channel blockers bind to amyloid
fibrils, and may result in exacerbation of heart failure.
Utility of β- blockers is not known
in amyloidosis. Patients with symptomatic bradyarrhythmia
should receive a permanent pacemaker
implantation.
With better
understanding of the mechanisms of amyloidosis, several
chemotherapy and immunotherapy are being tried. However, the
majority of patients with cardiac amyloidosis do not benefit
from these therapies. An earlier diagnosis, when the disease
burden is not high and the organ damage is not severe, may allow greater benefits of treatment.
In conclusion, increased awareness of cardiac
amyloidosis is warranted for early
diagnosis.
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