case study [chemistry] Results of Additional Diagnostic Procedures and

Tests
Shortness of Breath A chest X-ray revealed bilateral pleural effusions. An
in a 74-Year-Old Woman electrocardiogram showed normal sinus rhythm. A
Sean M. Hussey, MD, Frank H. Wians, Jr., PhD, MT(ASCP), transthoracic echocardiogram revealed a dilated left
DABCC, FACB atrium, an increase in right-sided filling pressure, and
Department of Pathology, University of Texas Southwestern mild to moderate mitral regurgitation. The left ventricular
Medical Center, Dallas, TX ejection fraction (LVEF) was within normal limits.
DOI: 10.1309/YDG28LC23XQJ0MMV
Questions:
Patient 1. What is (are) this patient’s most striking clinical and
74-year-old Caucasian woman. laboratory result(s)?

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Chief Complaint
Progressive increase in episodic shortness of breath for
the past 2 weeks.
History of Present Illness
The patient had been in her normal state of health until 2
weeks ago when she noticed that she had difficulty catching
her breath while walking. She was used to walking 2 miles
without difficulty, but was now becoming short of breath
after just 100 yards. The symptoms were progressing and
over the past 3 days the patient stated that she was short of
breath lying down. She had always slept with only 1 pillow,
2. How do you explain the patient’s most striking clinical
and laboratory result(s)?
3. What condition(s) does this patient’s laboratory and
other findings suggest?
4. What is the pathophysiology of this patient’s disease?
5. What are the clinical manifestations of this patient’s
disease?
6. What is the prognosis for this patient?
7. What is the most appropriate treatment for this patient?
Principal Laboratory Findings

Test Patient’s “Normal”

T1
but was now requiring 2 pillows. The patient also reported
Result Reference Range
an 8 to 10 pound weight gain over the past 6 weeks.
Hematology
WBC count 9.7 4.1-11.1 x103/µL
Past Medical History RBC count 4.19 4.01-5.31 x103/µL
Moderately controlled hypertension for the past 50 years. Hemoglobin 12.0 12.1-16.1 g/dL
Hematocrit 38.3 36.8-48.7%
Platelet count 244 174-404 x103/µL
Past Surgical History Differential: Neutrophils 62 35-80%
Benign parotid gland tumor removed in 1963. Lymphocytes 33 20-50%
Monocytes 4 2-12%
Eosinophils 1 0-7%
Drug History Basophils 0 0-2%
Diovan HCT, once a day; aspirin, 325 mg tablet, prn. Coagulation
PT 10.3 9.8-11.9 sec
INR 0.9
Family/Social History PTT 31.8 23.0-32.5 sec
The patient’s father died at age 56 from a heart attack sec- D-Dimer 0.7 0-3 mg/L
ondary to coronary artery disease. Her mother died at age 77 Chemistry
Sodium 136 135-145 mEq/L
secondary to colon cancer. Her brother died at age 49 from Potassium 3.6 3.6-4.0 mEq/L
an unknown cancer, and her sister died at age 68 from acute Chloride 101 98-109 mEq/L
renal failure secondary to diabetes mellitus. The patient has 4 CO2 25 22-31 mEq/L
BUN 11 7-21 mg/dL
children, all of whom are alive and healthy. She had no his- Creatinine 0.5 0.6-1.2 mg/dL
tory of smoking, alcohol abuse, or blood transfusion. AST 34 13-40 U/L
ALT 28 10-40 U/L
Total protein 7.1 6.3-8.2 g/dL
Physical Examination Albumin 4.2 3.5-5.2 g/dL
408 Vital signs: temperature, 35.8°C; heart rate, 82 beats per Total bilirubin 0.7 0.2-1.3 mg/dL
minute; respiratory rate, 18 breaths per minute; blood Direct bilirubin 0.1 0.0-0.3 mg/dL
BNP 827 <100 pg/mL*
pressure, 157/64 mmHg. The patient was well-nourished
and in no acute respiratory distress (oxygen saturation of *A BNP value <100 pg/mL is generally not consistent with a diagnosis of decompen-
sated heart failure; a BNP value >400 pg/mL is often seen in patients with advanced
95% on room air). Her current weight was 126 pounds. or decompensated heart failure due to left ventricular systolic or diastolic dysfunc-
The patient’s physical exam was normal with clear respi- tion; a BNP value between 100 pg/mL and 400 pg/mL may be difficult to interpret in
patients with concomitant diseases that can affect BNP levels, such as COPD and PE;
ratory sounds and no lower extremity edema. and, BNP results must always be evaluated in concert with other patient-specific clin-
ical and laboratory findings.
WBC, white blood cell; RBC, red blood cell; PT, prothrombin time; INR, International
Principal Laboratory Results Normalized Ratio; PTT, partial thromboplastin time; BUN, blood urea nitrogen; AST, aspar-
[T1]. tate aminotransferase; ALT, alanine aminotransferase; BNP, B-type natriuretic peptide.

laboratorymedicine> july 2004> number 7> volume 35 ©

Possible Answers: Characteristics of Pleural Fluid
1. A progressive dyspnea on exertion (the patient was un-
able to walk 100 yards without getting short of breath);
Transudates and Exudates

PF Characteristic Transudate Exudate

T2
orthopnea; a chest X-ray with bilateral pleural effusions;
an increased right-sided filling pressure on Protein, g/dL <3
LD, U/L <200 >200
echocardiogram; and a markedly increased EDTA-plasma Glucose, mg/dL >60
B-type natriuretic peptide (BNP) level. WBC count/mm3 <1,000
Cholesterol, mg/dL <45 >45
[Protein]PF:[Protein]S <0.5 >0.5
2. Dyspnea on exertion. The causes of shortness of [LD]PF:[LD]S <0.6 >0.6
breath during physical exertion include: 1) pulmonary dis- [Glucose]PF:[Glucose]S 1.0
ease [eg, malignancy, asthma, chronic obstructive Associated diseases Biventricular HF Pneumonia
with venous HTN Lung abscess
pulmonary disease (COPD), pulmonary embolus (PE)]; 2) Nephrotic syndrome Pancreatitis

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cardiac disease [eg, congestive heart failure (CHF), mitral
valve prolapse]; 3) deformity of the chest wall; and 4) dis-
eases associated with weakness of the respiratory muscles.
Orthopnea. Orthopnea, or shortness of breath while lying
down that is relieved with elevating the head, is most
often secondary to left ventricular cardiac failure. Other
etiologies include pulmonary congestion, asthma, COPD,
pulmonary infection, chronic cough, obesity, and abdomi-
nal distension. Pleural effusions on X-ray. The differen-
tial diagnosis of a pleural effusion is extensive; however,
thoracentesis to obtain pleural fluid and analysis of the
fluid for certain constituents allows the fluid to be catego-
rized as a transudate or an exudate [T2]. Transudates
occur when there is an imbalance between hydrostatic and
oncotic pressures (eg, in patients with heart failure in
whom the hydrostatic pressure of the fluid in the
peritoneal tissue becomes higher than the oncotic pressure
of the fluid in the pleural space causing the movement of
fluid from the peritoneum into the pleural space), while
exudates are defined by the presence of at least 1 of the
following criteria: 1) [protein]pleural fluid:[protein]serum ratio
> 0.5; 2) [LD]pleural fluid:[LD]serum ratio > 0.6; 3) [LD]pleural
1
fluid >200 U/L. The classification of a pleural fluid as a
transudate or exudate can be useful in suggesting
additional testing for differentiating between various diag-
noses. In the case of this patient, the effusions were too
small to warrant a thoracentesis. Therefore, the differential
diagnosis must include conditions associated potentially
with either a transudative or an exudative pleural fluid,
including CHF, liver cirrhosis, nephrotic syndrome, infec-
tion (bacterial, viral, mycobacterial), drug-induced (the
most common being treatment with amiodarone or nitro-
furantoin), sarcoidosis, systemic lupus erythematosis
(SLE), rheumatoid arthritis, pancreatitis, and PE.
Elevated BNP. B-type (or brain, the tissue in which it was
first discovered) natriuretic peptide (BNP) is a small pro-
tein (32 amino acids) produced following the cleavage of
a larger precursor protein (proBNP) that yields the physio-
logically inactive N-terminal proBNP molecule (NT-
proBNP) and the physiologically active hormone, BNP
[F1]. The family of natriuretic peptides includes atrial na-
triuretic peptide (ANP), BNP, and C-type natriuretic pep-
tide (CNP), all of which are involved in the regulation of
blood pressure and fluid homeostasis.2 The basic functions
of the natriuretic peptide hormones are: natriuresis, diuresis,
Peritoneal dialysis Pancreatic pseudocyst
Atelectasis TB
Urinothorax Actinomycosis
Pleurisy
Asbestosis
Malignant
mesothelioma
Lymphoma
Meigs syndrome*
Lung cancer
Pneumothorax
*Triad of benign fibroma (or other ovarian tumors) with ascites and large pleural effu-
sions. PF, pleural fluid; LD, lactate dehydrogenase; WBC, white blood cell; S, serum;
HF, heart failure; HTN, hypertension; TB, tuberculosis.
and vasodilation. Among the natriuretic peptides however,
BNP has been shown to be the most stable to
degradation, and the most diagnostically specific for
identifying patients with CHF and abnormal left ventricu-
lar function.3,4 The right ventricle of the heart pumps
blood directly to the lungs against a much lower resist-
ance to blood flow compared to the left ventricle which
must pump blood to all other parts of the body against a
much greater resistance to blood flow. Thus, patients with
CHF can have abnormal left ventricular function or mitral
regurgitation [ie, failure of the mitral (or bicuspid) valve
to prevent blood from flowing back into the left atrium
from the left ventricle]. The principal hemodynamic
measure of left ventricular function is the left ventricular
ejection fraction (LVEF). The LVEF is determined by M-
mode or 2D echocardiography and a normal functioning
left ventricle ejects through the aorta >50% of its end di-
astolic blood volume. Both BNP and NT-proBNP are ele-
vated in patients with signs and symptoms of HF and
abnormal left ventricular function (LVF) [F2 and F3] or
LVEF [F4A and F4B] according to the scheme for evaluat-
ing the severity of CHF developed by the New York Heart 409
Association (NYHA).3-5 However, mitral regurgitation,
trauma, abdominal or thoracic surgery, subarachnoid hem-
orrhage, certain brain disorders, and diabetic nephropathy
have all been shown to raise natriuretic peptide levels.6
Moreover, elevated BNP levels (>80 pg/mL) in patients
with an acute coronary syndrome are associated with a
higher incidence of death, new or progressive CHF, and
new or recurrent myocardial infarction.7 Our patient had a
normal LVEF, but mild to moderate mitral regurgitation,

© laboratorymedicine> july 2004> number 7> volume 35

 D R I S
9 M S
0 K S
R
S
1
C
G
H 2N-
H F
P L C C L 10 0
G S
1
P G
S A 0
proBNP G
C
K
S 7 S V
0 8 G L
Q 10 8
Y T L 0 V R
R A 7 K M R
P 6 P H — C OOH
R S

Cleavage

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D R I S
M S
K S
R S
C
G
F
1 1
0
7
0
7
6
C C L
H 2N- H P L G S P G S A S Y T L R A P R —C OOH C
S G K
V
G
Q L
V R
M R
NT-proBNP P K BNP H —C OOH
H 2N- S
(physiologically inactive) (physiologically active)

[F1] Formation of BNP (32 amino acids) and NT-proBNP (76 amino acids) from cleavage of the proBNP (108 amino acids) precursor molecule.

thus accounting for her markedly elevated EDTA-plasma
BNP level. The diagnostic accuracy of BNP as a screening
test for CHF depends on the nature of the population being
screened. As expected, the diagnostic accuracy (ie, sensitiv-
ity and specificity) of BNP in identifying patients with heart
failure or LV systolic dysfunction is higher in symptomatic
primary care patients than in individuals selected from a
cross-section of a community or general population [T3].8
3. Most likely diagnosis: congestive heart failure (CHF).
The constellation of our patient’s clinical and laboratory find-
ings, including dyspnea on exertion, orthopnea, bilateral

Healthy De
cre
as
Asymptomatic
ing
LV
No SOB w/ or w/o exercise F an
Normal LVF dI
NYHA I nc
rea
Asymptomatic w/LVD sin
gS
Asymptomatic ev
No SOB w/ or w/o exercise eri
ty
Abnormal LVF of
NYHA II HF
Compensated CHF
Asymptomatic
SOB w/exercise
Abnormal LVF NYHA III
Decompensated CHF
410
Symptomatic
Marked SOB w/exercise
Abnormal LVF
NYHA IV
Refractory CHF
Symptomatic at rest
SOB w/o exercise
Abnormal LVF even w/R x

[F2] The evolution of the clinical stages of congestive heart failure (CHF) according to the classification scheme developed by the New York
Heart Association (NYHA). SOB, shortness of breath; LVD, left ventricular dysfunction; LVF, left ventricular function; Rx, therapy.

laboratorymedicine> july 2004> number 7> volume 35 ©

pleural effusions, increased right-sided cardiac filling pres-
1600

[Natriuretic Peptide], pg/mL

sure, mild to moderate mitral regurgitation, and an elevated NT-proBNP
plasma BNP level makes CHF the most likely diagnosis. 1200
BNP

4. Pathophysiology of CHF. Congestive heart failure is 800

the result of an alteration of Starling forces in the cardiac
contractile myocytes. This alteration is most often related 400
to an index event. That event could be acute, as occurs
0
with an acute myocardial infarction, or chronic, such as Healthy HTN I II III IV
long-standing hypertension or mitral valve disease. The [CHF Classification, NYHA Class]
patient had both chronic hypertension and mitral regurgi-
tation. With mitral valve insufficiency, increased loading
[F3] Relative concentrations of B-type natriuretic peptide (BNP) and

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conditions (ie, increased blood requirements by the tissues
brought on by increased exercise resulting in a higher
heart rate as the heart works harder to keep up with the
demand for blood) lead to abnormal chemical signals
being sent to the cardiac myocytes and fibroblasts that
cause myocyte hypertrophy and an increase in collagen
deposition in the heart wall, a process known as “remodel-
ing.”9 Myocytes elongate eccentrically and consequently
the cardiac chamber dilates. This leads to alterations in
the anatomical relationship between the papillary heart
muscles and the valve leaflets, which worsens both the
valve abnormality and volume overload (dilation) of the
heart chambers. Over time, the chamber dilation exceeds
the myocyte hypertrophy and leads to increased cardiac
wall tension and systolic dysfunction. Long-standing hy-
pertension, on the other hand, results as an increase in the
cross-sectional thickness of individual myocytes. Thus,
CHF occurs when the heart is incapable of maintaining a
cardiac output sufficient to accommodate metabolic
requirements for oxygenated blood. When this occurs,
heart rate, pulse rate, blood pressure, and the release of
N-terminal pro-BNP (NT-proBNP) in healthy patients, patients with
hypertension (HTN), or congestive heart failure (CHF) of variable
severity (Class I, least severe to Class IV, most severe) according to
the CHF classification scheme developed by the New York Heart
Association (NYHA).
natriuretic peptides increase to compensate for these
changes. Over time, however, these mechanisms may fail
to relieve the stress on the heart and when this occurs, de-
compensated CHF of variable severity results in a medical
emergency requiring prompt medical intervention. The
severity of CHF is gauged typically using the classifica-
tion scheme developed by the New York Heart Association
(NYHA) [F2].
5. Clinical manifestations of CHF. Congestive heart fail-
ure can manifest itself clinically by a number of non-spe-
cific symptoms including fatigue, decreased appetite, and
increased heart rate. The principal clinical hallmarks of
CHF include pulmonary and peripheral edema from sodium

A B
Abnormal LVEF

[BNP] = 100 pg/mL

[NT- proBNP ] = 125 pg/mL

411

[F4] A) Inverse relationship between NT-proBNP and left ventricular ejection fraction (LVEF) (modified from Reference 3; solid line corresponds
to an NT-proBNP concentration of 125 pg/mL; dotted lines encompass patient groups with an abnormal LVEF (ie, <50%). B) Inverse
relationship between BNP concentration and LVEF (modified from Reference 4; solid line corresponds to an LVEF of 50%; dotted line
corresponds to a BNP concentration of 100 pg/mL). Note that some patients with an abnormal LVEF (ie, <50%) have a BNP
concentration less than a cutoff value of 100 pg/mL.

© laboratorymedicine> july 2004> number 7> volume 35

 Diagnostic Performance of BNP as
a Screening Test for Heart Failure*
Type of Patient Population
T3
Diagnostic Parameter General Symptomatic PC
Sensitivity 76a 97b
Specificity 87a 84b
PPV 16 70
NPV 98 98
*Modified from Reference #8. aAt a BNP cutoff value of 17.9 pg/mL. bAt a BNP cutoff
value of 76.8 pg/mL. BNP, B-type natriuretic peptide; PC, primary care; PPV, positive
predictive value; NPV, negative predictive value.
and water retention. In addition, because of the inadequate
supply of blood to perfuse all vital organs, blood is
shunted away from the periphery to compensate for this
deficiency. The decreased blood flow to the muscles and
limbs leads to fatigue and peripheral edema. Moreover, the
stomach also receives less blood, which can lead to diges-
tive problems. Symptoms more specific for cardiac disease
that are frequently seen in patients with CHF are shortness
of breath, peripheral edema (most often in the lower ex-
tremities), wheezing, and persistent cough. As heart muscle
function declines in patients with CHF, pulmonary pres-
sures increase, ultimately progressing to fluid accumulat-
ing in the air spaces (alveoli) of the lung. Once this
happens, breathlessness, cough, and wheezing soon follow.
Eventually, right-sided heart failure develops followed by
leakage of fluid into the peripheral soft tissues. In addition,
decreased renal function secondary to the lack of adequate
renal blood perfusion leads to sodium and water retention
by the kidneys and a worsening of the pre-existing periph-
eral edema.
6. The prognosis for patients with CHF is variable
depending on several factors, including age, severity of
the heart failure, and the overall health of the patient.
Two-thirds of patients with CHF die within 5 years, while
20% of patients with CHF die within 12 months of diag-
nosis. Moreover, the prognosis is slightly worse in men
than in women. The biggest medical concern in patients
with CHF is lethal cardiac arrhythmia, which occurs at a
rate 9 times higher than that of the general population.
Despite advances in the treatment of hypertension and
myocardial infarction, the survival rate for patients with
CHF has not improved dramatically. Patients can improve
their survival by closely monitoring their diet, controlling
412 their weight, and not smoking or consuming large
amounts of alcohol.
7. The appropriate treatment for patients with CHF usu-
ally consists of a combination of prescription medications
and lifestyle changes. Controlling dietary intake of fats,
limiting alcohol intake, and smoking cessation can
laboratorymedicine> july 2004> number 7> volume 35
increase the effectiveness of any pharmacologic treatment
regimen. Multiple medications have been shown to im-
prove both cardiac function and CHF symptoms.
Angiotensin converting enzyme (ACE)-inhibitors are con-
sidered by many to be the first-line of CHF therapy and
act by blocking the production of angiotensin, a hormone
with significant vasoconstrictor activity, thus lowering the
heart’s workload by causing vasodilation. Diuretics are
often prescribed to increase the amount of sodium and
water excreted by the kidneys. This will help decrease the
total body fluid volume and decrease cardiac workload.
Digoxin, an inotropic agent that increases the force of the
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heart’s contractions, is used to improve cardiac contractil-
ity and decrease atrial fibrillation. Other medications
used in the treatment of patients with CHF include
vasodilators, beta blockers, calcium channel blockers, and
anticoagulants. In some patients, insertion of an
automated implantable cardioverter defibrillator (AICD),
or pacemaker, under the skin below the left or right collar
bone may be beneficial in reducing mortality due to car-
diac arrhythmias.
Patient’s Treatment and Course
The patient was continued on Diovan HCT and started on
Lasix, Toprol, and daily aspirin therapy. She was referred
for follow-up to the cardiology service. She had several
follow-up BNP measurements and 6 months following the
initiation of her therapy, her plasma BNP level was 178
pg/mL.
Keywords: congestive heart failure, dyspnea, orthop-
nea, B-type natriuretic peptide, pleural fluid,
transudate, exudate
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©