Lithium-induced Ebstein’s Anomaly

Abstract

Ebstein’s anomaly (EA) is a rare congenital cardiac defect that occurs when the tricuspid valve leaflets fail to delaminate from the ventricular myocardium, they adhere to the underlying myocardium. Multiple etiologies such as genetic mutation in NKX2-5, family history of congenital cardiac anomalies, and exposure to teratogen such as lithium are associated with this rare cardiac anomaly. In our case, we present an undiagnosed adolescent male with EA who was exposed to lithium during organogenesis.

INTRODUCTION

Ebstein’s anomaly (EA) is an uncommon cardiac birth defect that comprises <1% of cardiac congenital abnormalities with an estimated risk of one in 200,000 live births.[1,2] EA is characterized by malformation including the right ventricle (RV) and tricuspid valve (TV). The abnormalities in EA include posterior and septal tricuspid leaflets’ adherence to the underlying myocardium, displacement of the TV downward (apically), dilation of atrialized portion of RV, with varying degrees of hypertrophy and thinning of the wall, dilation of the right atrioventricular junction and anterior tricuspid leaflet’s tethering, fenestrations, and redundancy.[1,3]

The RV in EA is divided into two regions; the part directly involved with the malformation (the inlet portion), which is functionally integrated with the right atrium (RA), and the part that is not involved with the malformation, which consists of the functional RV consisting of the trabecular and outlet portions.[3] The atrialized RV can dilate disproportionately accounting for more than half of the RV volume in extreme cases rather than the usual one-third of the total RV volume.[3] The anatomic severity of EA is assessed by echocardiography (ECHO) and graded into mild, moderate, or severe based on the degree of RV dilatation and the amount of tethering and displacement of the tricuspid leaflets. This is an imprecise but simple classification.[4] The presentation ranges from severe symptomatic form during the newborn era to incidental diagnosis later in life, including late adulthood.[5] In our presented report, EA was diagnosed at a later stage in life although having being a congenital malformation induced by a teratogen lithium bringing novelty to our case report.

CASE PRESENTATION

A 19-year-old Asian male of low socioeconomic class, of Indian origin came to our outpatient department accompanied by his relative with chief complaints of acute chest pain for 2 days associated with the feeling of pounding in the retrosternal area not relieving with rest. The patient also complained about fatigue and shortness of breath on exertion for the past month of grade II New York Heart Association. The patient had no history of diabetes mellitus, asthma, or hypertension. Family history revealed the consumption of 2 tablets of lithium carbonate 300 mg each daily by the patient’s deceased mother during the first trimester of pregnancy for bipolar disorder and stopping it at the end of the second trimester. The patient is currently not under any medication for any chronic disease and has no history of surgery in the past.

On examination, the patient was conscious, cooperative, and well-oriented with time, place, and person. Heart rate, blood pressure, and SpO2 of 184 beats per min was regular bilaterally, 130/96 mmHg, and 82% in room air, respectively. The palpatory findings of the chest wall revealed precordial asymmetry and systolic thrill on the left lower sternal border. The physical examination revealed lower extremity edema. Systolic murmurs and splitting of first and second diastolic sounds were heard during inspiration on auscultation.

Two-dimensional ECHO revealed a largely dilated RA with an area of 33.5 cm² [Figure 1], moderately dysfunctional RV with an area of 14.9 cm² [Figure 2], apical displacement of the septal tricuspid leaflet by 18 mm², “sail-like” morphology of the anterior tricuspid leaflet [Figure 3] and severe tricuspid regurgitation. Pulmonary arterial systolic pressure was 16 mmHg confirming the diagnosis of EA with the Great Ormond Street Echocardiography (GOSE) score of 1.5. The inferior vena cava was 1.5 cm collapsing with respiration. Other findings included the left atrium area of 14.2 cm² and the left ventricle area of 16.2 cm² with the left ventricular ejection fraction of 60%. The pulmonary, aortic, and mitral valves measured 20, 14, and 12 mm, respectively. No atrial septal defect or patent foramen ovale was observed.

Figure 1.

Two-dimensional echocardiography showing a hugely dilated right atrium with an area of 33.5 cm²

Figure 2.

Two-dimensional echocardiography showing four chamber view

Figure 3.

Two-dimensional echocardiography showing apical displacement of the septal tricuspid leaflet by 18 mm² and flail anterior tricuspid leaflet

The patient was prescribed esmolol to control tachyarrhythmia, and furosemide to obtain relief from edema. The patient was advised and counseled for surgical follow-up but denied it and wanted to adhere to only medical management. The patient was referred to an electrocardiologist in a higher center for further specialty care.

During 2 weeks of follow-up, the patient’s condition was not improving but also not deteriorating.

DISCUSSION

EA accounting for <1% of congenital cardiac anomalies, has variable natural history depending on the degree of anatomical abnormalities, with patients growing to adulthood who might exhibit less severe disease and are asymptomatic for a long time.[6] Incidental findings of the EA can occur in late adolescence as seen in our case although being present at birth.[3] During the development of the myocardium when the TV leaflets fail to delaminate from the ventricular myocardium, they adhere to the underlying myocardium, leading to EA.[3] Various clinical features presented by a patient of EA include cyanosis, right-sided heart failure, arrhythmias, and sudden cardiac death.[3] In our case, the patient presented with exertional dyspnea and lower extremity edema. In EA, dyspnea occurs due to the result of right to left shunting with resultant hypoxemia.[1] The association of EA with a genetic mutation in NKX2-5, family history of congenital cardiac anomalies and maternal intake of lithium is already attributed in the known literature.[1,7] In our case, maternal consumption of lithium during the period of organogenesis seems to be the reason resulting in EA in our patient. Lithium use has been effective against long-term maintenance for bipolar disorder and has been frequently prescribed to women of childbearing age.[8] With a narrow therapeutic range of 0.5–1.2 mmol/l, lithium levels decrease by 24% and 36% in the first and second trimesters, respectively.[8] However, in our case, the overuse of lithium during the period of organogenesis led to the formation of EA. Observational studies have indicated an increased risk of congenital cardiac defects with the use of lithium in early pregnancy.[9] Patorno et al., also described the dose-dependent association between increased risk of lithium and cardiac malformation beyond 900 mg per day.[9] The novelty of our presented case remains that a 600 mg (two doses of 300 mg each) per day dose for 6 months (first trimester and end of second trimester) of lithium was successful in its teratogenicity leading to EA. Antenatal care of women with psychiatric disorders can be a challenge but it should also focus on the awareness of potent teratogenic drugs like lithium. Switching to different medical management is not only recommended but also a necessity.

Surgical correction of the right side of the heart including the TV is the definitive management of EA.[7] Less than 5% of patients with EA survive beyond the age of 50 years without any surgical intervention.[7,10] In our case, the GOSE score was found to be 1.5 which represents an 8% mortality rate yet we counseled the patient for surgical management to which the patient did not consent. In cases where the patient is reluctant to have surgery or multiple complications arise that are unfavorable for surgery, medical management, and weekly follow-up are the only options available for the patient’s wellness.

CONCLUSION

EA being a rare presentation can be presented clinically in late adolescence. Women diagnosed with bipolar disorder and taking lithium must be provided with a better alternative, especially those who are planning for pregnancy. Lithium remains a potent teratogen with a narrow therapeutic range, which may lead to EA if consumed during the period of organogenesis. Studies suggest that lithium beyond 900 mg per day increases the risk of association with cardiac malformation. However, EA was observed in our case with only 600 mg per day intake for a 6-month duration. Pregnant females must be screened for any risk of exposure to teratogens.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.