Zebra Body Formation Due to Drug-Induced Phospholipidosis Observed on Electron Micrographs

A 66-year-old woman presented with exacerbation of heart failure and reduced ejection fraction (EF; 24%). The patient had been taking carvedilol (≥7.5 mg daily) for over 4 years. She was given a clinical diagnosis of isolated cardiac sarcoidosis based on the following: JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis;¹ localized wall thinning of the left ventricle (the mid-anterior and base, mid-inferior walls) and reduced EF observed on transthoracic echocardiography; elevated uptake on ¹⁸F-fluorodeoxyglucose positron emission tomography; late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging; and no coronary artery stenosis detected on cardiac computed tomography. Electron microscopy of the myocardial tissue revealed zebra bodies, which are layered myelin-like structures within lysosomes (Figure A,B) and a characteristic feature of Fabry disease. However, no genetic abnormalities that are diagnostic criteria for Fabry disease were observed. Clinical and laboratory features consistent with Fabry disease, such as corneal verticillata and low α-galactosidase A activity levels in the white blood cells, or other causative diseases of zebra bodies, were not detected. LGE presented diffusely in the mid-wall (Figure C,D) and native T₁ times extended in all segments except the base-anterior segment (Figure E).

Figure.

(A,B) Electron microscopy images of myocardial tissue revealed zebra bodies. The layered plate structure had a period of approximately 6 nm (B). (C,D) Late gadolinium enhancement (arrowheads) of the short-axis (C) and 2-chamber (D) views on cardiac magnetic resonance imaging. (E) Native T₁ (normal reference range 1,150–1,350 ms).

Drug-induced phospholipidosis (DIPL) causes phospholipid accumulation in the lysosome. Carvedilol has been identified as a DIPL-inducing agent in vitro.² Thus, the zebra bodies observed in the myocardial tissue of the present patient were considered to be caused by DIPL. The present case potentially facilitates electron microscopy-based diagnosis.

Disclosures

This study was supported by scholarship funds from Otsuka Pharmaceutical Co., Ltd. K.T. is a member of Circulation Reports’ Editorial Team.

IRB Approval

This study was approved by Shimane University Faculty of Medicine (No. 4818).

References

• 1.   Terasaki F, Azuma A, Anzai T, Ishizaka N, Ishida Y, Isobe M, et al; on behalf of the Japanese Circulation Society Joint Working Group. JCS 2016 guideline on diagnosis and treatment of cardiac sarcoidosis: Digest version. Circ J 2019; 83: 2329–2388.
• 2.   Muehlbacher M, Tripal P, Roas F, Kornhuber J. Identification of drugs inducing phospholipidosis by novel in vitro data. ChemMedChem 2012; 7: 1925–1934.