A Protean Protein

Eighteen months after symptom onset, the patient presented to the emergency department with dyspnea, orthopnea, and lower extremity edema. B-type natriuretic peptide was 1564 pg/mL. Transthoracic echocardiography showed a severely dilated and hypertrophied left ventricle. Left ventricular ejection fraction was 20%. A furosemide infusion was initiated. Angiography of the coronary vessels was not performed. Congo red stain of an abdominal adipose biopsy was negative for amyloid.

On hospital day five, he developed gangrenous changes in his right first toe. CT angiography of the abdomen and lower extremities demonstrated patent three vessel runoff to the foot with an infrarenal aortic thrombus. Heparin infusion was started. On hospital day 10, the patient developed expressive aphasia and somnolence, prompting intubation for airway protection. MRI and MR angiography (MRA) of the brain and cerebral vessels revealed multiple bilateral acute ischemic strokes (Figure 1) without flow limiting stenosis in cerebral vessels.

These clinical developments lead to an important opportunity to rethink this patient’s working diagnosis. The new diagnosis of heart failure in this young patient with polyneuropathy raises suspicion for an infiltrative cardiomyopathy such as amyloidosis, sarcoidosis, or Fabry disease. Of these, Fabry disease is the least likely because it is typically characterized by a painful burning sensation in response to specific triggers. Although polyneuropathy and heart failure may be concurrently observed with both sarcoidosis and amyloidosis, the absence of an apparent arrhythmia make amyloidosis the more likely of these two diagnoses. The development of an arterial thrombus and multiple strokes may represent emboli from a cardiac thrombus.

Cardiac imaging and tissue biopsy of the heart or other affected organs would distinguish between these diagnostic possibilities. An abdominal adipose biopsy negative for amyloid does not rule out amyloidosis, as the test is approximately 80% sensitive when cardiac amyloidosis is present and varies depending on the etiology of the amyloid protein (ie, light chain vs transthyretin). Evaluation of cardiac amyloid in the setting of peripheral neuropathy should include echocardiography (as was performed here) and repeat testing for a monoclonal protein.

If clinical suspicion of a paraprotein-associated disorder remains high and both SPEP and sFLC are normal, it is important to obtain a 24-hour UPEP and immunofixation. A monoclonal protein can be overlooked by SPEP and serum immunofixation if the monoclonal protein is composed only of a light chain or if the monoclonal protein is IgD or IgE. In these rare circumstances, sFLC analysis or 24-hour UPEP and immunofixation should mitigate the potential for a falsely negative SPEP/IFE. These studies are normal in this case, which argues against the presence of a monoclonal protein.

Transesophageal echocardiography showed grade IV atheromatous plaque within the descending thoracic aorta with mobile elements suggesting a superimposed thrombus; there was no intracardiac shunt or thrombus. MRA of the neck and great vessels was normal.

Testing for heparin-induced thrombocytopenia (HIT) was sent due to thrombocytopenia and the presence of thrombosis. An immunoassay for antiheparin-platelet factor 4 (anti-PF4) antibodies was substantially positive (optical density 2.178); however, functional testing with a washed platelet heparin-induced platelet activation assay was negative. Anticoagulation was changed to argatroban due to concern for HIT. Dry gangrenous changes developed in all distal toes on the right foot and three toes on the left foot. A right radial artery thrombus formed at the site of a prior arterial line.