Healing the orphaned heart: heart failure in a patient with glucose-6-phosphate dehydrogenase deficiency

Abstract

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are not represented in clinical trials for heart failure. Moreover, many of the recommended medications can cause haemolysis in this group of patients. We present the case of a 71-year-old woman with G6PD deficiency admitted for acute non-ischemic heart failure with reduced ejection fraction. Our experience showed that a combination of ethacrynic acid and spironolactone is safe and effective for relief of volume overload in this group of patients. Studies are needed to determine whether the morbidity and mortality benefits of established heart failure regimens extend to patients with G6PD deficiency.

Background

Despite hundreds of clinical trials on heart failure (HF), there are still huge gaps about its management in populations with specific comorbidities.¹ Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most prevalent enzyme deficiency with an estimated 400 million people affected worldwide, are not represented in these studies.² Moreover, many of the recommended cardiac medications can cause haemolysis in this group of patients, such as sulfa-containing diuretics and possibly aspirin (in high doses) and isosorbide dinitrate.³ The presence of G6PD deficiency in our patient with acute non-ischemic HF with reduced ejection fraction (HFrEF) provided a unique therapeutic challenge. We need studies to determine whether the morbidity and mortality benefits of established HF regimens extend to patients with G6PD deficiency.

Case presentation

A 71-year-old African-American woman presented to the hospital with worsening exertional dyspnoea associated with orthopnoea and lower extremity oedema for 3 weeks. She had a long-standing history of hypertension and documented G6PD deficiency with prior episodes of haemolysis. She was a former cigarette smoker and had family members with G6PD deficiency, hypertension and diabetes mellitus. Vital signs measurement revealed a blood pressure of 150/73 mm Hg, pulse rate of 70 bpm, respiratory rate of 24 breaths/min, temperature of 36.6°C and 97% saturation on room air. She was comfortable at rest. Her physical examination showed distended jugular veins, inspiratory crackles in bilateral lung bases, a laterally displaced apical impulse and bipedal oedema.

Investigations

The ECG showed left ventricular hypertrophy and inferolateral T-wave inversions. Chest radiography revealed cardiomegaly and mild pulmonary oedema. The metabolic panel and troponin levels were normal but the B-type natriuretic peptide was increased at 826.5 pg/mL. Echocardiography showed a dilated left ventricle with an ejection fraction (EF) of 30% and mild right ventricular systolic dysfunction. Coronary artery catheterisation revealed normal coronary circulation.

Treatment

Ethacrynic acid at 50 mg daily was chosen for diuresis. She improved after a day but still had dyspnoea, so we added spironolactone. Subsequently, metoprolol succinate and losartan were included in the regimen.

Outcome and follow-up

Repeat chest radiography showed resolution of pulmonary oedema. The patient's laboratory results during her hospital stay did not show signs of haemolysis nor worsening kidney function. She did not develop ototoxicity and was discharged home asymptomatic.

Discussion

G6PD deficiency is the most prevalent enzyme deficiency. While this X linked disorder most commonly affects people from Africa, Asia, the Mediterranean and the Middle East, the complications of G6PD deficiency may now occur in most countries owing to increasing international travel.⁴ X linked disorders are usually thought to affect only males, but because of the high frequency of G6PD deficiency, homozygous females contribute about 10% to the phenotypic prevalence.⁴ Moreover, 10% of heterozygous females also manifest the disease due to unequal X-chromosome activation.⁴

G6PD catalyses the conversion of glucose-6-phosphate to 6-phosphogluconate and the formation of reduced nicotinamide adenine dinucleotide phosphate (NADPH). In red cells, this G6PD-mediated pathway is the only source of NADPH. As NADPH is important in the replenishment of the antioxidant glutathione, patients with G6PD deficiency are particularly vulnerable to haemolysis in the presence of oxidative stress.

This enzyme also modulates vascular function by increasing the levels of nitric oxide, a vasodilator that also prevents platelet aggregation, leucocyte adhesion and smooth muscle proliferation.⁵ While there is no question on the haematological effects of G6PD deficiency, the impact of this condition on the pathophysiology of cardiovascular disease is less clear. The limited available data based on mice studies indicate that, in the face of cardiac stress, the adverse effects of G6PD deficiency may outweigh potential protective effects, such as decreased cholesterol synthesis and superoxide production.⁶ These studies show increased susceptibility to ventricular dilation in response to myocardial infarction or pressure overload-induced HF.⁶

Results of human studies on the cardiovascular effects of G6PD deficiency are less consistent. In a 1967 study, 7.2% of patients affected by coronary artery disease carried the G6PD A- variant without an associated increased frequency of hypertension.⁷ However, higher blood pressure levels were observed among African-American men carrying the same genetic variant.⁸ Ironically, one cohort study of 1756 men carrying the more severe Mediterranean mutation showed decreased mortality from heart disease, although this may be a result of selection bias.⁹ The effect on other ethnic groups is unknown.

As our patient was volume overloaded, a loop diuretic was indicated and we had to choose among the available drugs. We assumed that our patient had the G6PD A- variant, which is most common among patients with African descent.¹⁰ This variant is associated with a moderate level of enzyme deficiency and an increased risk of haemolysis with oxidative drugs.

In the USA, four loop diuretics are available: furosemide, bumetanide, torsemide and ethacrynic acid. The first three are usually preferred over ethacrynic acid because of the latter's increased propensity to cause metabolic alkalosis and ototoxicity.¹¹ Ethacrynic acid, however, is the only loop diuretic available that does not contain a sulfa moiety. This is particularly important as sulfa drugs can cause haemolysis in patients with G6PD deficiency. In addition, ethacrynic acid has a venous dilatory effect like furosemide and this effect immediately relieves symptoms of pulmonary congestion even before diuresis can occur.¹¹

We added spironolactone based on the Randomized Aldactone Evaluation Study (RALES) trial which showed reductions in all-cause mortality, sudden cardiac death and HF hospitalisations with the use of spironolactone in patients with HF and EF less than 35%.¹² As aldosterone decreases G6PD expression and nitric oxide production resulting in impaired endothelial function, we postulate that spironolactone may be particularly beneficial for patients with HF with G6PD deficiency.⁵

Metoprolol succinate and losartan were included in the regimen based on the American College of Cardiology Foundation and the American Heart Association recommendation that an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker and a β blocker should be given to patients with HFrEF in Stage C and New York Heart Association (NYHA) Class I-IV to reduce morbidity and mortality.¹

At present, there is no established guideline for treating patients with G6PD deficiency with HF. They represent an orphan population with regards to inclusion in clinical trials. Our case illustrates that a combination of ethacrynic acid and spironolactone is safe and effective in treating symptoms of acute non-ischemic HFrEF due to volume overload. Studies are needed to determine whether the morbidity and mortality benefits of established HF regimens extend to patients with G6PD deficiency.

Learning points.

• Many of the recommended heart failure medications can cause haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• The combination of ethacrynic acid and spironolactone is safe and effective for relief of volume overload in patients with G6PD deficiency with heart failure.

• Studies are needed to determine whether the morbidity and mortality benefits of established heart failure regimens extend to patients with G6PD deficiency.