A male patient, aged 62, is evaluated in the internal medicine clinic for a four-month his… — USMLE Step 3

A male patient, aged $62$ , is evaluated in the internal medicine clinic for a four-month history of progressive dyspnea on exertion, leg swelling, and spontaneous bruising. He also reports bilateral hand numbness that predominantly affects the thumb, index, and middle fingers. His only known medical history is essential hypertension. Blood pressure is $110/70$ mm Hg, heart rate is $88$ /min, and respiratory rate is $16$ /min. Jugular venous pressure is elevated at $10$ cm H $_2$ O. Pulmonary auscultation is clear. Cardiac examination reveals a regular rhythm with an S4 gallop and no murmurs. Dermatologic examination shows periorbital ecchymoses and pinch purpura on the upper chest. Bilateral $2+$ pitting edema is present up to the knees.

Laboratory studies reveal:
Hemoglobin: $10.2$ g/dL
Platelet count: $165,000$ /mm $^3$
Creatinine: $1.8$ mg/dL
Calcium: $10.8$ mg/dL
Prothrombin time: $13$ seconds
Activated partial thromboplastin time: $30$ seconds
Urinalysis: $3+$ protein

Electrocardiogram demonstrates normal sinus rhythm with low voltage QRS complexes in the limb leads. Echocardiogram demonstrates severe concentric left and right ventricular thickening with a left ventricular ejection fraction of $55\%$ and a diffuse, granular sparkling appearance of the myocardium.

Which of the following is the most likely diagnosis?

Immunoglobulin light chain (AL) amyloidosisAnswer
B
Transthyretin (ATTR) amyloidosis
C
Cardiac sarcoidosis
D
Hypertensive heart disease
E
Disseminated intravascular coagulation

Answer

Immunoglobulin light chain (AL) amyloidosis

The correct answer is Immunoglobulin light chain (AL) amyloidosis. This patient presents with restrictive cardiomyopathy, nephrotic-range proteinuria, hypercalcemia, carpal tunnel syndrome, and periorbital ecchymoses, which forms the classic constellation of AL amyloidosis. The echocardiogram shows severe biventricular thickening with a granular appearance, which, paradoxically paired with low voltage QRS complexes on ECG, is highly specific for cardiac amyloidosis. The pathognomonic periorbital purpura (often referred to as 'raccoon eyes') results from amyloid deposition in blood vessel walls causing severe capillary fragility. Furthermore, the hypercalcemia, anemia, and significant renal dysfunction strongly suggest an underlying plasma cell dyscrasia (such as multiple myeloma) driving the AL amyloidosis.

Step-by-Step Solution

Identify the primary cardiac pathophysiology.

The combination of right heart failure symptoms, severe biventricular thickening with preserved ejection fraction, and a sparkling granular echocardiogram appearance indicates a restrictive cardiomyopathy.

Recognizing the core cardiovascular syndrome is the first step in narrowing the differential diagnosis.

Correlate the echocardiogram findings with the electrocardiogram.

The discrepancy between thick ventricular walls on echocardiography and low voltage QRS complexes on ECG is highly specific for an infiltrative myocardial disease, ruling out simple hypertensive hypertrophy.

This specific diagnostic pairing differentiates infiltrative processes from true myocyte hypertrophy.

Synthesize the systemic physical examination findings and laboratory abnormalities.

The patient exhibits carpal tunnel syndrome, periorbital ecchymoses, hypercalcemia, and nephrotic-range proteinuria with normal coagulation profiles.

Amyloidosis is a systemic disease, and determining the specific subtype relies on identifying the pattern of extra-cardiac organ involvement.

Differentiate the underlying etiology based on the synthesized clinical picture.

The combination of systemic vascular fragility (purpura) and signs of a plasma cell dyscrasia (hypercalcemia, renal injury, proteinuria) definitively points to AL amyloidosis rather than ATTR amyloidosis.

Premature closure after identifying 'amyloidosis' leads to diagnostic error; the specific subtype dictates entirely different management.

Key Concept

Differentiating subtypes of amyloidosis by recognizing the pathognomonic multisystem presentation of Immunoglobulin light chain (AL) amyloidosis, specifically capillary fragility and plasma cell dyscrasia findings.

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