Effusive Reasoning

Abstract

KEY WORDSpattern recognition–analytic reasoning–problem representation–clinical diagnostic reasoning

Full text

CLINICAL PRACTICE
Exercises in Clinical Reasoning
Effusive Reasoning
Brandon Erickson, BS
1
, Gurpreet Dhaliwal, MD
2
, Mark C. Henderson, MD
3
, Ezra Amsterdam, MD
4
,
and Joseph Rencic, MD, FACP
1,5
1
Tufts University School of Medicine, Boston, MA, USA;
2
Department of Medicine(University of California, San Francisco and the San Francisco
Veterans Affairs Medical Center, San Francisco, CA, USA;
3
Department of Internal Medicine(University of California, Davis Medical Center,
Sacramento, CA, USA;
4
Department of Internal Medicine, Division of Cardiovascular Medicine(University of California, Davis Medical Center,
Sacramento, CA, USA;
5
Department of Internal Medicine(Tufts Medical Center, Boston, MA, USA.
KEY WORDS: pattern recognition; analytic reasoning; problem
representation; clinical diagnostic reasoning.
J Gen Intern Med 26(10):1204–8
DOI: 10.1007/s11606-011-1785-7
© Society of General Internal Medicine 2011
A71-year old man was referred for recurrent bilateral,
transudative pleural effusions of unknown etiology.
Over the previous five months, he had had multiple admis-
sions during which the effusions were drained a total of 15
times, with each procedure removing 1–2 L from both sides.
When the effusions were present, he noted mild dyspnea and
orthopnea, but these symptoms resolved after thoracent-
esis. He also noted anorexia and a 30-pound weight loss over
the same time period. He denied paroxysmal nocturnal
dyspnea, chest pain, lower extremity edema, lightheaded-
ness, presyncope, palpitations, fever, chills, night sweats,
nausea, vomiting or changes in his bowel and bladder habits.
During his initial admission, an electrocardiogram (ECG)
demonstrated a normal sinus rhythm with non-specific ST-
TW changes but no other abnormalities. An echocardiogram
demonstrated a normal ejection fraction, mild mitral and
tricuspid regurgitation, normal right and left ventricle size
with septal ventricular hypertrophy (14 mm, normal 7–
11 mm), and mild right and left atrial enlargement. Left
and right heart catheterizations were normal. After his
initial admission, treatment with bumetanide 2 mg twice
daily did not prevent reaccumulation of the effusions. He
had undergone three thoracenteses in the last week, most
recently on the day prior to his admission.
The presence of chronic, recurrent, bilateral transudative
pleural effusions raises several possibilities. Heart failure is the
most common cause of bilateral transudative pleural effusions.
The presence of biatrial enlargement and normal ventricular
systolic function in an elderly man with hypertension makes
diastolic dysfunction an important consideration. The septal
hypertrophy could imply an infiltrative process, but may also
occur in hypertrophic or hypertensive cardiomyopathy. Ne-
phrotic syndrome can present with pleural effusions but the
weight loss and lack of peripheral edema make it less likely.
Hepatic hydrothorax can uncommonly occur in patients
without ascites, but bilateral effusions would be unusual.
Considering the patient’s advanced age and significant weight
loss, malignancy remains on the differential, although cancers
typically cause exudative effusions. The weight loss makes
hypothyroidism, in which the pleural effusions are usually
small and asymptomatic, unlikely as well.
The problem representation is an abstract one-sentence sum-
mary of the key features of the case synthesized in the clinician’s
mind and only sometimes explicitly spoken or written. At this point,
the problem representation is refractory, recurrent, bilateral
transudative pleural effusions and weight loss. In the traditional
medical encounter the problem representation is usually developed
after collecting clinical data. This case is more typical of referrals,
transfers, and some consultations, where the problem may be
clearly defined at the outset (the very first sentence ofthis case). In
these instances, data collection focuses on verifying or further
refining this representation and narrowing the list of possibilities.
He has a history of prostateand renal cell carcinomas that
were resected in 1993. He was not treated with chemother-
apy or radiation. The only other past medical history was
hypertension and chronic kidney disease (baseline blood
urea nitrogen 65 mg/dl and creatinine 2.4 mg/dl), which had
been stable over the past year. He worked as a schoolteacher
for most of his life, except for 7 years in the 1960s when he
worked as a machinist building parts for airplanes (which
exposed him to asbestos). He did not smoke,drink alcohol, or
use illicit drugs. On admission his only medications were
bumetanide, multivitamins, and fish oil. He previously took
lisinopril, hydrochlorothiazide, montelukast, and albuterol
inhaler, but discontinued these 2 months earlier based on his
doctor’s recommendation. Over the last 5 months his blood
pressure had gradually decreased from 140/90 to70/50 mm
Hg. Approximately one month prior to the current admis-
sion, he was started and then maintained on a stable dose of
bumetanide 2 mg twice daily. His family history was
significant for stomach cancer, colon cancer, diabetes, and
coronary artery disease. He was born and raised in the United
States and had not traveled recently.
His personal history of renal cell and prostate cancers, as well
as his strong family history, increase concern for malignancy. It
would be unusual for a solid tumor to cause a transudative
effusion or to present only as bilateral effusions without evidence
of metastases. Asbestos typically causes unilateral, exudative
effusions and pleural plaques; his distant and limited exposure
history makes asbestosis unlikely. The development of slowly
progressive, asymptomatic hypotension raises the possibility of
chronic conditions that impair cardiac output or lower systemic
vascular resistance, such as end-stage liver disease or adrenal
JGIM
Received February 18, 2011
Revised May 17, 2011
Accepted May 25, 2011
Published online July 15, 2011
1204

insufficiency, although he does not have risk factors for either
condition. In an elderly patient with profound but slowly
progressive hypotension, an early consideration is pump failure
due to prior myocardial infarction or progressive cardiomyopathy,
commonly caused by uncontrolled hypertension or valvular
disease. The latter two possibilities are unlikely given the
relatively normal echocardiogram several months earlier.
On admission he was a thin, well-appearing elderly gentle-
man with a temperature of 35.8°C, heart rate of 100 beats per
minute sitting, blood pressure 60/46 mm Hg, respiratory rate
of 20 breaths per minute, and oxygen saturation of 97% on
room air. There was no significant change in blood pressure or
heart rate from sitting to standing positions. The mucous
membranes were moist. There was no lymphadenopathy.
Cardiac exam revealed diminished heart sounds with no
murmurs, rubs, or gallops. His jugular venous pressure was
normal; no Kussmaul’s sign or pulsus paradoxus was detected.
His chest was clear to auscultation; no accessory muscle use,
decreased breath sounds, or dullness to percussion were
noted. His abdominal, neurologic, skin and musculoskeletal
exams were normal. He had no lower extremity edema.
The current exam reveals no signs of left or right heart failure,
end-stage liver disease, or nephrotic syndrome. Having under-
gone thoracentesis the day previously, he no longer has evidence
of pleural effusions. Overdiuresis might explain the low blood
pressure and tachycardia, although in the past he had not
apparently responded to diuretics. Diminished heart sounds are
non-specific; but the combination of diminished heart sounds,
tachycardia, and hypotension brings to mind cardiac tamponade,
although this triad is seen in theminority of cases. While previous
testing would have excluded a significant pericardial effusion, the
possibility of this seriousmanifestation developing at this point in
the illness warrants consideration. Constrictive pericarditis can
present with refractory transudative effusions without pulmo-
nary edema, normal left ventricular systolic function and
characteristic diastolic abnormalities on echocardiogram. How-
ever pericardial imaging on echocardiogram has significant
limitations and so should not be relied upon to exclude
constrictive pericarditis. However, these patients typically have
elevated jugular venous pressure with significant lower extremity
edema, and severe hypotension is unusual. At this point, three
leading problems have emerged: recurrent transudative pleural
effusions, weight loss, and severe hypotension.
Problem representations evolve over time–spanning minutes
in a patient encounter or days to months in complex undiag-
nosed cases. At this point the final solution must also explain
severe hypotension. The low blood pressure in combination with
decreased heart sounds triggers consideration of an emergent
condition (pericardial tamponade), but does not yield a unifying
diagnosis consistent with the physical examination (due to the
absence of jugular venous distension).
His chemistries were notable for blood urea nitrogen of
65 mg/dl (normal range 10–20) and creatinine of 2.5 mg/dl
(normal range 0.5–1.3). Bilirubin, alkaline phosphatase,
and transaminases were normal. His albumin was 3gm/dl
(normal range 3.4–4.8). His complete blood count and
coagulation studies were normal. His creatine kinase (CK),
and CK–MB fraction were normal, but the troponin I was
0.46 ng/ml (normal range <0.05). B-natriuretic peptide
(BNP) was 2,466 pg/ml (normal range 0–100). An early
morning cortisol was greater than 20ug/dl. Thyroid stim-
ulating hormone, angiotensin converting enzyme, and
antinuclear antibody levels were normal. Ferritin was
33 ng/ml (normal range 30–300), iron 20 μg/dl (normal:
49–181), total iron binding capacity 360 μg/dl (normal:
228–428), and iron saturation 6% (normal range 25–72).
Urinalysis was normal. An electrocardiogram (ECG) showed
sinus rhythm at 82 beats per minute, multiple premature
ventricular complexes, left atrial enlargement, and de-
creased voltage in the limb leads (Fig. 1). A chest x-ray
showed a normal heart size, bilateral hilar fullness, and
mild bilateral costophrenic angle blunting.
Figure 1. Admission ECG for current hospitalization.
1205Erickson et al.: Effusive ReasoningJGIM

The normal urinalysis and coagulation studies rule out
nephrotic syndrome and end-stage liver disease, respectively,
given the low pre-test probabilities for these conditions. The
elevated BNP suggests an underlying cardiac process, although
some BNP elevation might be expected from his reduced
glomerular filtration rate. The low voltage on ECG observed in
the limb leads suggests pericardial disease (particularly in a thin
patient), but typically such diseases lead to a diffuse reduction in
voltage. The extremely elevated BNP favors a myocardial process
such as restrictive cardiomyopathy over constrictive pericarditis.
A small proportion of patients with restrictive cardiomyopathies
present without elevated jugular venous pressure or lower
extremity edema. Infiltrative restrictive cardiomyopathies, in-
cluding sarcoidosis and amyloidosis, could also explain the
mildly elevated troponin due to direct myocardial injury.
Hemochromatosis would be an important consideration, but
his age, absence of diabetes or liver function abnormalities, and
low iron saturation exclude this diagnosis. His unchanged
chronic renal dysfunction and bland urine sediment lower the
concern for superimposed renal pathology. The cortisol level
excludes adrenal insufficiency as a cause of his hypotension.
The priority given to certain findings by the discussant drives
the revised problem representation and ensuing diagnostic
considerations. The decreased limb voltage on ECG and
elevated biomarkers are emphasized (although a number of
negative findings are integrated as well). What follows is a
comparison of two competing illness scripts (mental representa-
tions of diseases in memory)—constrictive pericarditis (dis-
cussed previously) and restrictive cardiomyopathy (new
hypothesis). Some laboratory values change disease probabil-
ities significantly, such as the normal urinalysis and serum
cortisol, while others are equivocal but suggestive. The signifi-
cantly elevated BNP and mildly elevated troponin suggest a
myocardial rather than pericardial disorder. The normal urinal-
ysis dissuades the discussant from linking the chronic kidney
disease to the final solution.
A transthoracic echocardiogram (Fig. 2)showed a left
ventricular ejection fraction of 40%, increased left ven-
tricular wall thickness, mildly reduced right ventricular
systolic function, normal sized right and left ventricles,
severe biatrial enlargement, increased right ventricular
systolic pressure of 40–50 mmHg (normal 15–25), and no
pericardial effusion. A computed tomography of the chest
demonstrated reaccumulation of bilateral pleural effusions
and no parenchymal infiltrates or lymphadenopathy.
The normal sized ventricles with mild systolic dysfunction and
severe biatrial enlargement suggest a restrictive cardiomyopathy.
The increased left ventricular wall thickness may be consistent
with his previous history of hypertension (particularly if uncon-
trolled) but decreased voltage in the limb leads contradict that
interpretation, once again raising suspicion for an infiltrative
cardiomyopathy. The absence of thoracic lymphadenopathy or
pulmonary infiltrates on CT make sarcoidosis unlikely; although
a rare presentation of isolated cardiac sarcoidosis can only be
excluded with an endomyocardial biopsy. As hemochromatosis
and sarcoidosis appear unlikely, amyloidosis emerges as a
leading diagnosis. The hypotension could be explained by
amyloidosis-associated autonomic neuropathy. Although normal
cardiac hemodynamic measurements by catheterization during
his initial hospitalization would not be expected, he may have
been hypovolemic at the time, leading to a falsely negative result.
The discussant notes the ventricular wall thickness and
paradoxically decreased limb voltage. This discrepancy is both at
odds with the illness script for hypertension-associated ventricular
hypertrophy and may have triggered a rule-of-thumb acquired from
experience (“LVH on echo with low voltage on EKG—think
infiltrative cardiomyopathy”). Although the case for amyloidosis
cannot be made stronger with the information at hand, its
probability is elevated by excluding the competing diagnoses of
sarcoidosis and hemochromatosis. Possible explanations for the
discrepancy between the original echocardiogram and the more
recent study include: incomplete original information (e.g. summary
instead of complete report, or even a synopsis such as “normal”);
variations in the patient’s physiology or image acquisition; or
evolution of the disease over time.
On hospital day 3 the patient reported dyspnea and
orthopnea. A chest x-ray showed worsening large bilateral
pleural effusions. A repeat computed tomography of the
chest demonstrated bilateral pleural effusions. Pleural fluid
was transudative with 450 nucleated cells; the differential
count was 90% lymphocytes, 7% monocytes, 1% neutro-
phils. Adenosine deaminase, cytology, gram stain, and acid-
fast bacilli culture of the fluid were all normal.
The rapidity of the accumulation could reflect intravenous
fluid administration for the patient’s hypotension. However, in
decompensated heart failure, it is unusual for such marked
pleural transudation to occur without any pulmonary edema,
suggesting the possibility of pleural disease as an additional
contributor to the effusions. Although the effusion is transuda-
tive, the preponderance of lymphocytic cells suggests chronic
pleural inflammation or invasion, as can be seen in amyloidosis.
The clinical picture and echocardiogram support a diagnosis of
restrictive cardiomyopathy secondary to amyloidosis. An endo-
myocardial biopsy could provide pathological confirmation.
On hospital day 4, a right heart catheterization showed a
mildly decreased cardiac output, and increased right atrial,
right ventricular, pulmonary arterial, and pulmonary
wedge pressures. Endomyocardial biopsy showed classic
apple green birefringence on Congo red staining in a
pattern consistent with amyloid, myocyte hypertrophy
and degenerative changes (Fig. 3). A SPEP showed moderate
hypoproteinemia, moderate hypoalbuminemia, and mod-
Figure 2. Transthoracic echocardiogram, apical four chamber
view, systolic phase of cardiac cycle.
1206 Erickson et al.: Effusive Reasoning JGIM

erate hypogammaglobulinemia. A serum immunofixation
electrophoresis showed a small band in the IgM and
corresponding kappa lane within a polyclonal background,
and two additional small bands in the lambda lane. A UPEP
and urine immunoelectrophoresis were both normal.
Serum free light chain assay showed normal kappa light
chain levels and an elevated lambda light chain level of
88.40 mg/L (normal range 5.70–26.30).
The patient deteriorated rapidly on hospital day 6, requir-
ing hemodynamic support with multiple vasopressors. A
repeat transthoracic echocardiogram showed an ejection
fraction of 20%, further biatrial enlargement, and increased
biventricular dysfunction and wall thickness. The patient died
on hospital day 9 prior to receiving treatment for amyloidosis.
The myocardial tissue was characterized post-mortem by the
Mayo Clinic laboratory as containing AL amyloid.
DISCUSSION
The development and refinement of a problem representation,
as highlighted in earlier articles in this series, is the critical
step that allows the clinician to match the patient’s words and
data with illness scripts in the physician’s memory.
1,2
The
traditional patient encounter requires sequential data collec-
tion to develop a problem representation. There are other
situations (e.g., consultation, referral, or transfer) in which an
explicit problem representation is presented at the outset, as
in this case. This early framing does not free the consulting
clinician from doing repeated or more in depth data collection
to verify the primary data; but subtly changes the major
cognitive duty from problem representation development to
problem representation verification/rejection and further
characterization. In return for having a large amount of data
acquired and filtered, the accepting physician must be mindful
of premature closure, confirmation bias, and framing effects
that may influence their thinking.
Thetextbookapproachforreachingadiagnosisisfinding
supporting evidence from the history, physical examination,
laboratory, and imaging studies that matches a particular illness
script. A complementary strategy highlighted less often but used
regularly in practice is the elimination of competing hypotheses.
Theoretically, the sum of all possible diagnoses must equal 100%.
In this case, when the discussant discovered features going
against constrictive pericarditis (e.g. lack of edema), restrictive
cardiomyopathy increased in probability. When no further
information supporting amyloidosis as the explanation for the
restrictive cardiomyopathy could be gleaned (e.g., nephrotic
syndrome or sensorimotor peripheral neuropathy), exclusion of
competing infiltrative cardiomyopathies (e.g., sarcoidosis and
hemochromatosis) bolstered the likelihood of amyloidosis. This
justified an invasive test, endomycardial biopsy, to confirm the
diagnosis. Both the “rule in”(textbook) and “rule out”(utilized in
this case) strategy require robust illness scripts buttressed by
literature searches when rare disorders are being considered.
The framework assumes that the ultimate unifying diagnoses
are mutually exclusive. However the clinician is frequently left
trying to bolster the case for Dx1 only by downgrading the
probability of Dx2 with the nagging feeling that an unsuspected
or unknown (either to the clinician or to medical science) diagnosis
(Dx3) explains the patient’s illness. There is no fail-proof way to
safeguard against this possibility, but the establishment of a clear
problem representation is the critical step in leveraging other
human and electronic resources to ponder the same question
before crossing a diagnostic or treatment threshold.
CLINICAL TEACHING POINTS
1. Unexplained recurrent transudative bilateral pleural effu-
sions should prompt an evaluation for constrictive peri-
carditis and restrictive cardiomyopathy after more
common causes, such as other cardiomyopathies, cirrho-
sis, nephrotic syndrome, and pulmonary embolism have
been excluded.
3
Unlike other cardiac causes, constrictive
pericarditis and restrictive cardiomyopathy sometimes
present without pulmonary edema.
4,5
2. Clinicians can use basic bedside, laboratory, and echocar-
diographic information to distinguish restrictive cardio-
myopathy from constrictive pericarditis. Though elevated
jugular venous pressure and peripheral edema are nearly
always associated with constrictive pericarditis, these
findings may be absent in cardiac amyloidosis.
4
In addi-
tion, a significantly elevated B-natriuretic peptide may
help distinguish intrinsic myocardial disorders such as
restrictive cardiomyopathy from constrictive pericarditis;
although the values may overlap in these two conditions
and lose specificity in patients with a reduced glomerular
filtration rate.
6–8
Ultimately, advanced echocardiographic
findings (particularly Doppler imaging) and hemodynamic
measurements by cardiac catheterization are required for
definitive diagnosis.
3. The pattern of biatrial enlargement with increased ventric-
ular wall thickness and normal ventricular size on echo-
cardiography suggests a restrictive cardiomyopathy, often
due to amyloidosis.
9
Common ECG abnormalities include
low limb lead voltage and a pseudoinfarct pattern.
10
4. The combination of restrictive cardiomyopathy and neurop-
athy is suggestive of amyloidosis. In this case, the progres-
sive hypotension raised suspicion for an autonomic
neuropathy. Although hypotension may be seen in 11–44%
of patients with amyloidosis, orthostatic hypotension is
unusual.
4,11
Figure 3. Right ventricular endomyocardial biopsy demonstrating
apple green birefringence.
1207Erickson et al.: Effusive ReasoningJGIM

5. Primary Amyloidosis (AL) is a rare plasma cell dyscrasia in
which the lambda or kappa light chains of antibodies are
overproduced and deposited in various organs (e.g., heart,
kidney, peripheral nerves), leading to dysfunction. AL
amyloidosis can only be diagnosed by tissue biopsy from
either the involved organs or abdominal fat pad.
12,13
6. The median survival for AL amyloidosis is six to nine
months in patients with heart failure, but may be as low
as 2 months in patients with persistent pulmonary pleural
effusions.
4,14,15
Conflict of Interest Statement: None disclosed.
Funding Source: None.
Corresponding Author: Joseph Rencic, MD, FACP; Department of
Internal Medicine(Tufts Medical Center, 750 Washington Street, Box
398, Boston, MA 02111, USA (e-mail: jrencic@tuftsmedicalcenter.
org).
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