Congenital Heart Disease and Thyroid Dysfunction: Combination,Association,and Implication

Abstract

Background:

Patients with congenital heart disease have higher prevalence of thyroid dysfunction due to embryonic and genetic coexistence. Marked changes in cardiac function occur secondary to alternations in thyroid hormone levels. Cardiac catheterizations or cardiac surgeries with cardiopulmonary bypass can cause abnormalities in the circulating hormones, in the absence of primary thyroid disease. Therefore, monitoring of thyroid function should be routinely performed in children with congenital heart disease. Thyroid hormone supplementation has been postulated as a possible therapeutic option; however, the therapeutic decisions should be made based on individual circumstances, symptoms, and the severity of the thyroid dysfunction.

Objectives:

To describe the correlation between congenital heart disease in children and thyroid dysfunction and the debate on monitoring, intervention, and treatment.

Methods:

PubMed, Clinical Key, and the Cochrane Library were searched using keywords relevant to congenital heart disease/surgery, cardiopulmonary bypass, thyroid hormones, sick euthyroid syndrome, and cardiac catheterization. Studies were limited to the English language and to children 0 to 18 years old. Studies in adults with important findings were reviewed as well. All clinical studies believed to have relevance were considered. All relevant studies were reviewed, and the most pertinent data were incorporated in this review.

Conclusion:

There is lack of significant evidence concerning treatment for thyroid dysfunction in children with a congenital cardiac diagnosis. Adequately powered studies are needed before a uniform recommendation about treatment can be made.

Keywords

congenital heart disease congenital heart surgery cardiopulmonary bypass thyroid hormones sick euthyroid syndrome cardiac catheterization

Thyroid Function

The thyroid hormones, thyroxin (T₄) and triiodothyronine (T₃), are synthesized and secreted by the thyroid gland via iodination of tyrosine residues into thyroglobulin. Production is stimulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary in response to hypothalamic thyrotropin-releasing hormone (TRH). Thyroxin can be considered as the prohormone of T₃, and it is converted to an active T₃ by deiodination. Triiodothyronine is five times more potent than T₄ with a much greater affinity for cellular thyroid receptors. About 80% of circulating T₃ is produced by this conversion in the liver and other tissues (except the cardiac myocyte); the remaining 20% is secreted directly by the thyroid gland. Both T₃ and T₄ are carried in the circulation bound to T₄-binding globulin, transthyretin, and albumin, which exert a negative feedback on the release of TSH and TRH. Triiodothyronine and T₄ bind to thyroid receptor proteins in the cell nucleus. As a nuclear transcription factor, T₃ also contributes to the up- and downregulation of genes. Target organ responses to thyroid hormones include increased oxygen consumption and basal metabolic rate and have influence on calcium, phosphorus, carbohydrate, protein, and lipid metabolism. The end-organ effects are based both on circulating levels of active T₃ and on the level of thyroid receptor occupancy. The activity of the deiodination enzymes is therefore crucial in the production of intracellular T₃ and critical for the maintenance of normal cellular activity.^1,2

The heart and vasculature are major target organs for thyroid hormone action, and marked changes occur in cardiac function when changes in thyroid hormone levels occur. Nongenomic effects of thyroid hormones include enhancement of actin polymerization, modulation of mitochondrial respiration, effects in messenger RNA translation, and alternations to some protein kinase activity. Genomic T₃ mechanisms include effects on the myosin-associated ATPase gene, leading to an indirect effect on myosin chain expression.¹ Both transcriptional and nontranscriptional effects of thyroid hormone may act in concert to modulate the function of the myocardium and the vascular system under physiologic and pathologic conditions³ (Table 1).

Table 1.

The Thyroid Hormones Interactions With the Cardiovascular System.^a

Cardiomyocytes—genomic	T3 binds to thyroid hormone nuclear receptors which regulate transcription of specific cardiac genes. Positively regulating gene expression of α-myosin heavy chain, sarcoplasmic reticulum Ca2+-ATPase, Na+/K+-ATPase, β1-adrenergic receptor, voltage-gated potassium channels. Enhanced contractile function and diastolic relaxation in the heart regulate intracellular calcium cycling. Expression of the prohormone genes for each natriuretic peptide secreted by cardiac myocytes is regulated by thyroid hormone and is altered with changes in blood pressure and disease states that affect cardiac function. Effect on the action potential duration and repolarization. The pacemaker-related genes and hyperpolarization-activated cyclic nucleotide-gated channels 2 and 4 are transcriptionally regulated by thyroid hormone influencing diastolic depolarization, increase in heart rate, QT interval changes, and ventricular irritability.
Cardiomyocytes—nongenomic	Direct modulation of membrane ion channels. Changes in various membrane ion channels for sodium, potassium, and calcium, effects on actin polymerization, adenine nucleotide translocator 1 in the mitochondrial membrane, and a variety of intracellular signaling pathways in the heart and vascular smooth muscle cells.
Cardiovascular hemodynamics—genomic	Adrenomedullin, a polypeptide of 52 amino acids, is a potent vasodilator transcriptionally regulated by thyroid hormone.
Cardiovascular hemodynamics—nongenomic	Effect on membrane ion channels and endothelial nitric oxide synthase, which serves to decrease systemic vascular resistance. Relaxation of smooth muscle leads to decreased arterial resistance and pressure, which thereby increases cardiac output. Increased endothelial nitric oxide production may result from the T3-mediated effects on the protein kinase pathway. Decreased systemic vascular resistance and increased resting heart rate, left ventricular contractility, and blood volume decreased resistance in peripheral arterioles through a direct effect on vascular smooth-muscle cells and decreased mean arterial pressure.
Kidneys	Thyroid hormone acts first to lower systemic vascular resistance which causes mean arterial pressure to decrease causing increased renin synthesis and secretion. T₃ also directly stimulates renin substrate synthesis in the liver which increases blood volume, preload, and contributes to the characteristic increase in cardiac output. Hypothyroidism is often accompanied by a rise in diastolic blood pressure. Because cardiac output is low, the pulse pressure is narrowed. The increase in diastolic pressure occurs with low serum renin levels. Increases erythropoietin synthesis → increase in red cell mass → increase in blood volume and preload.
Hematology	Serum erythropoietin concentrations are increased in hyperthyroid patients, although the hematocrit and hemoglobin levels remain normal because of the concomitant increase in blood volume. In contrast, serum erythropoietin levels are low in hypothyroidism and may explain the normochromic, normocytic anemia found in as many as 35% of those patients
Metabolic	Thyroid hormones increase basal metabolic rate in almost every tissue and organ system in the body, and the increased metabolic demands lead to changes in cardiac output, systemic vascular resistance, and blood pressure. Development of hypercholesterolemia (catabolism of cholesterol into bile is mediated by the enzyme cholesterol 7α-hydroxylase which is a liver-specific enzyme that is negatively regulated by T₃ and may contribute to the decreased catabolism and increased levels of serum cholesterol associated with hypothyroidism). The increased serum lipid levels potentially associated with increased cardiovascular risk. Dyslipidemia together with the diastolic hypertension associated with hypothyroidism may predispose the patient to atherosclerosis.
Immunology	Some evidence exists that autoimmune disease may play a role in primary pulmonary hypertension. Effect of thyroid hormone to decrease systemic vascular resistance may not occur in the pulmonary vasculature. Both pulmonary hypertension and atrioventricular valve regurgitation have been documented to occur with a surprisingly high prevalence. It may be that some component of the “right heart failure” and peripheral edema that can accompany hyperthyroidism is caused by this reversible change in pulmonary artery pressure.

^aAdopted from Klein and Danzi.²⁴

Congenital Hypothyroidism and Cardiac Defects

Congenital hypothyroidism is a prevalent disorder in neonates, affecting 1 per every 2,500 to 4,000 infants.⁴ It represents the most common cause of avoidable mental retardation in infancy and is diagnosed early by neonatal screening.⁵ Furthermore, congenital hypothyroidism with delayed TSH elevation is a common form of transient thyroid dysfunction among premature infants.⁶

The incidence of extrathyroidal congenital anomalies varies depending on genetics, the geographical region, and ethnicity. Congenital heart disease (CHD) is considered the most common congenital malformation, estimated at approximately 8% to 12% across the world, and is the most frequent malformation associated with congenital hypothyroidism. The fact that in most studies cardiac involvement has been considered to be the most common coexisting abnormality in patients with congenital hypothyroidism raises the suspicion that some common contributing factors may be present in cardiac and thyroid development during the embryonic period. Different nuclear transcription factors are involved in heart and great vessel organogenesis and they are common to embryonic development of the thyroid gland. Point mutations and missense changes have been identified in patients with CHD and thyroid dysgenesis.^4,5

Down syndrome is the most common chromosomal abnormality that is compatible with life, with reported incidences ranging from 1/700 to 1/800 live births. Congenital heart disease, which is the most frequent systemic malformation, is present in 16% to 62% of individuals with Down syndrome. An increased prevalence of thyroid disease, particularly subclinical hypothyroidism, has been reported in children with Down syndrome. In those children, a possible concomitant hypothyroidism-related impairment of cardiac function may worsen their clinical condition and can ultimately affect their life expectancy.⁷

Thyroid hormone is critical for normal neurocognitive development in young infants, and even transient hypothyroidism can cause adverse neurodevelopmental outcomes. In a population of infants with CHD who already bear a high risk of long-term developmental delay, detection of hypothyroidism, even of a transient nature, may be even more consequential, and routine periodic monitoring of thyroid function may be necessary to reduce the risk of neurodevelopmental disabilities.⁸

Sick Euthyroid Syndrome

Severe pathological stress can cause abnormalities in the circulating thyroid hormone levels in the absence of a primary thyroid disease; this is called the sick euthyroid syndrome (SES) or nonthyroidal illness.⁹ It is not clear whether SES promotes recovery and is adaptive or whether it is a direct result or cause of the illness and organ failures and therefore maladaptive.¹⁰ The nadir occurs at 24 to 48 hours with recovery by day 5. Thyroid-stimulating hormone recovery often precedes restoration in T₃ and T₄ levels. Axis suppression can sometimes last for a week. The sickest patients show the greatest biochemical abnormality, those with complications showing a more prolonged depression and a delayed recovery.¹

The most common pattern is a decrease in total and unbound T₃ with normal levels of TSH and T₄. This is classified as SES-1. The deiodination from T₄ to T₃ via peripheral (hepatic) enzymes is impaired, leading to a decrease in T₃ and an increase in reverse T₃ that is biologically inactive. Serum T₃ concentrations might fall by more than 60% and remain low for up to 8 days after surgery.³ Elevated serum levels of steroids as part of a stress response may influence the deiodinase activity and TSH and T₃ response in SES.^3,9

Very sick patients may show a dramatic fall in total T₃ and T₄ levels; this state is called the low T₄ syndrome or SES-2 and has a poor prognosis. For example, neonates exposed to bypass and hypothermia uniformly show a pattern of SES-2¹¹; the metabolism of T₄ may further be influenced by a decrease in thyroid binding globulin levels. Tissue-specific thyroid hormone bioactivity is reduced during cellular hypoxia and contributes to the low T₃ syndrome of severe illness.⁹ In both SES-1 and SES-2, serum levels of TSH are impaired and do not increase in reaction to low T₃ or T₄ levels. Patients with low or undetectable TSH show increased morbidity and mortality. Additionally, the response of TSH to TRH is impaired in SES. The degree of SES seems to have a significant influence on a patient’s outcome under various conditions.⁹

Cardiac Abnormalities in Hypothyroidism

Thyroid hormone deficiency may cause abnormalities in both myocardial structure and function which include left ventricular hypertrophy, reversible diastolic abnormalities, raised systemic vascular resistance, and reduced contractile response.¹ Triiodothyronine changes the performance characteristics of various channels in the heart, and changes in intracellular levels of calcium and potassium can increase inotropy and chronotropy. Alterations in calcium flux are implicated in a number of pathophysiological states seen in cardiac critical care, ranging from depressed systolic function, poor diastolic relaxation, to myocardial “stun.” Myocardial stun is a reversible phenomenon frequently seen following cardiac surgery and resulting in a prolonged postischemic ventricular myocyte dysfunction. Myocardial stun is relatively more important in neonates due to their immature myocardium. Triiodothyronine is an agent that increases intracellular calcium during systole and enhances its removal in diastole; therefore, it improves neonatal myocardial function and possible restoration of neonatal myocardium to near normal function. In addition, T₃ may be responsible for catecholamine responsiveness (possibly via receptor upregulation and improvement of left ventricular function) and influence sinus node automaticity (via changes in sodium and potassium flux rather than via adrenergic mechanisms).^1,2 Furthermore, those changes in ion channels may prolong the cardiac action potential and the QT interval. These consequences predispose the patient to ventricular irritability and, in rare cases, acquired torsade de pointes.³

In addition to the well-recognized action of the thyroid hormone of increasing peripheral oxygen consumption and substrate requirements, which causes a secondary increase in cardiac contractility, the hormone increases cardiac contractility directly. Triiodothyronine decreases systemic vascular resistance by dilating the arterioles resistance of the peripheral circulation. The vasodilation is due to a direct effect of T₃ on vascular smooth muscle cells, which promotes relaxation. Studies of the various components of the adrenergic receptor complex in plasma membranes have shown that all the different receptors are altered by changes in thyroid status.³

As a result of the decrease in systemic vascular resistance, the effective arterial filling volume falls, causing an increase in renin release and activation of the angiotensin–aldosterone axis. This, in turn, stimulates renal sodium reabsorption, leading to an increase in plasma volume. Thyroid hormone also stimulates erythropoietin secretion. The combined effect of these 2 actions causes an increase in blood volume and preload, which further increases cardiac output.³

Cardiac Interventions and Thyroid Response

The pattern of thyroid response largely differs in the pediatric population undergoing cardiac intervention. There is a close correlation between the age of the patient, cardiopulmonary bypass (CPB) time, postoperative morbidity, and the degree of thyroid response.

Cardiac surgery (with or without CPB) induces a marked and a persistent depression of circulating thyroid hormones during the postoperative period both in adults and in children.¹¹ The extent to which this depression occurs and its association with postoperative mortality and morbidity are not known.¹² Most of the life-threatening CHDs have a neonatal presentation and usually a neonatal cardiac surgery carries a higher operative risk and a more troublesome postoperative period than a surgery performed at older age.¹¹

In general, the illness severity is correlated with the severity of thyroid dysfunction. It is possible that the fall in serum levels of thyroid hormones may be due to ultrafiltration during CPB, hemodilution associated with CPB, and suppression of pituitary–thyroidal axis.¹² A number of postoperative factors (including the use of peritoneal dialysis, thoracic duct ligation, albumin/fresh frozen plasma replacement, somatostatin for decreasing lymphatic drainage) may have affected the course of the development of postoperative hypothyroidism and need to be further analyzed in a controlled fashion in future studies. Prolonged chest tube drainage can be an important issue after pediatric cardiac surgery due to the loss of clotting factors and thyroid-binding globulin in chest tube output.¹³ Dopamine infusions additionally induce or aggravate partial hypopituitarism and SES by a direct inhibition of anterior pituitary function through inhibitory dopamine receptors, resulting in diminished TSH release. The concentration of plasma selenium in children undergoing CPB decreases significantly, resulting in a diminished deiodinase activity and a subsequent reduction in the conversion of T₄ to T₃.⁹ Maturational variation in endocrine function, mainly occurring within the first month of life, may have an additional influence on postsurgical hormonal response.¹¹

It is well known that cardiac surgery and CPB lead to a generalized systematic inflammatory response syndrome, resulting in an increased postoperative morbidity and mortality and an organ failure. Inflammatory cytokines (particularly interleukin 6) have been linked to the development of SES by inhibition of a peripheral conversion of T₄ to T₃.⁹

Studies that have concentrated on the effects of CPB on thyroid function in neonates showed a nadir of the TSH, T₃, and T₄ levels on the first or second day after surgery, followed by normalization on the fifth or seventh day. Plumpton et al demonstrated that younger children (less than three months of age) with longer CPB time showed prolonged ventilation after CPB and lower free T₃ levels.¹⁴ Talwar et al found that low levels of T₄ were correlated with a greater postoperative morbidity, a prolonged postoperative course, prolonged mechanical ventilation, and increased inotropic requirements following CPB. They also found that there was a difference in levels of T₄ between the survivors and nonsurvivors.¹² Bettendorf et al showed that the group with the lower T₃ median concentration had a longer stay in the intensive care unit (ICU) and required more mechanical ventilation support. Their cumulative inotropic support was significantly higher.¹⁵ Brogan et al found that those who had longer mechanical ventilation also had lower T₄ levels.¹⁶ Linder et al reported that infants who had lower levels of T₄ underwent more procedures (cardiac catheterization, surgery; 1.4 vs 2.4). They support the fact that the degree of hypothyroxinemia directly correlates with the severity of illness and the postoperative course and is reversible after two weeks.¹⁷ In contrast to previous studies that implicate the dilution effects of CPB solutions as causing changes immediately postoperatively, Marks et al showed that CPB and aortic clamp times did not affect the degree of SES.¹⁰

In Fontan patients, after completion of total cavopulmonary connections and separation of the pulmonary circulation from the systemic circulation, T₄ decreased in the more severely ill patients, but there is no evidence of a change in the non-Fontan patients when the two groups were analyzed separately. The Fontan patients also have greater and more prolonged effects of T₃.¹⁸

Several nonspecific insults which occur in all major surgeries such as fasting, anesthetic agents, and surgical stress may also contribute to a decline in the levels of free T₃. In 2001, Mainwaring et al demonstrated a decline in the levels of T₃ in serum by more than three-fifths in infants who undergo the first stage of the Norwood reconstruction for hypoplastic left heart syndrome. These peri- and postoperative T₃ levels are substantially lower when compared to a normal value range for age-matched normal patients.¹⁹ Mainwaring et al demonstrated an 80% decrease in TSH, free T₃, and thyroglobulin levels in neonates following CPB and hypothermia.²⁰

At last, infants with CHD are commonly exposed to excess iodine from administration of iodinated contrast media (ICM) during cardiac catheterization as well as topical application of iodine-containing antiseptics and dressings; hence, this is a vulnerable population.²¹ The severity and duration of hypothyroidism in infants with frequent exposure to excess iodine from multiple sources has not been well characterized. Furthermore, impaired renal function during the postoperative period in infants requiring intervention for CHD might hamper urinary clearance of iodine and further increase the risk of hypothyroidism, and the association between impaired renal function and hypothyroidism in infants with CHD has also not been well studied. In a recent case–control study of children exposed to iodine, hypothyroidism was diagnosed in 25% of the infants. There is a strong association between the number of procedures with exposure to iodine and the subsequent development of hypothyroidism. This finding was noted by Thaker et al in their prospective study of iodine-induced hypothyroidism in infants with CHD.⁸ In a recent large case–control study of adults exposed to ICM followed up for a six-year period in Taiwan, Kornelius et al noted a significantly greater risk of hypothyroidism in patients with two or more exposures to ICM.²² Hypothyroidism was also reported in 19 (19%) of 99 infants with congenital cardiac malformations two weeks after coronary arteriography in a Spanish prospective study.²³

Amiodarone and Thyroid Function

Amiodarone is a highly effective antiarrhythmic drug used for the treatment of both atrial and ventricular cardiac rhythm disturbances. Because of its high iodine content, amiodarone can cause changes in thyroid function. Amiodarone inhibits the conversion of T₄ to T₃ as well as the fact that iodine released from amiodarone metabolism can directly inhibit thyroid gland function.²⁴

In general, patients treated with amiodarone should have thyroid function (specifically TSH) testing periodically throughout therapy. Should hypothyroidism develop, the patient should be treated with l-thyroxine (which does not impair the antiarrhythmic effect). Two forms of amiodarone-induced hyperthyroidism exist—Type 1 hyperthyroidism occurs in patients with preexistent thyroid disease and occurs more often in regions where iodine intake is low. Type 2 hyperthyroidism is caused by an inflammatory process that causes increased release of thyroid hormones from a previously normal thyroid gland. No uniform consensus exists on the proper form of treatment. It is important to measure serum TSH, total and free T₄, and total T₃ as well as antithyroid antibodies. Although most treatment protocols suggest cessation of the amiodarone and use of thioureas in relatively high doses, neither of these interventions have been shown to lead to predictable benefits.²⁴ The different studies evaluating thyroid function in pediatric cardiac patients are summarized in Table 2.

Table 2.

List of Studies Evaluating Thyroid Function in Pediatric Cardiac Patients.

Study	Population	Year	Major Findings	Recommendations
Brogan et al	37 infants undergoing repair of congenital cardiac defects	1997	Infants requiring CPB were divided into two groups: group 1 received povidone-iodine; group 2 received chlorhexidine as a topical preoperative antiseptic. Group 3 required thoracotomy without CPB and received povidone-iodine as a preoperative antiseptic. There was a significant decrease in TSH concentrations immediately after surgery in the two CPB groups. This change was significantly greater than the change in TSH concentration in the thoracotomy group. Total T3 and T4 concentrations decreased by postoperative day 2 in both groups 1 and 2, and the changes were significant compared with group 3. Total T3 and T4 concentrations increased significantly in all groups after postoperative day 2, with no significant difference between the three groups.	CPB has a more significant effect on thyroid hormone metabolism than does the use of iodine-based preoperative antiseptic.
Linder et al	21 full-term infants with major cardiac anomalies who survived for more than a month	1997	Following catheterization or surgery, six infants had raised thyrotropin concentrations; three had low T₄ concentrations. Two of those infants were treated with l-thyroxine.	Iodine exposure during cardiac catheterization or surgery may induce transient hypothyroidism in term infants.
Bettendorf et al	132 children with congenital heart defects undergoing cardiac surgery	1997	Postoperative urinary iodine excretion increased significantly. Thyroid hormone plasma concentrations were lowest after cardiopulmonary bypass operations and in patients treated with dopamine. In patients with postoperative low T3 plasma concentrations, the period of mechanical ventilation and intensive care treatment was significantly prolonged. The cumulative doses of inotropic and vasoactive agents and furosemide were significantly higher in this patient group.	Possible benefits of thyroid hormone replacement therapy need to be thoroughly examined.
del Cerro et al	99 children under three years of age, with congenital cardiac disease	2000	The occurrence of multiple malformation syndromes was the most clearly associated risk factor (P < .01) not only in the development of post angiography hypothyroidism but also in longer hormonal dysfunction.	Thyroid function should be tested in every patient with multiple malformation syndrome who undergoes angiocardiography with iodinated contrast agents.
Mainwaring et al	14 newborns with hypoplastic left heart syndrome scheduled for first stage reconstruction	2001	Significant decreases in levels of free and total T₃ during the early postoperative period. These changes in levels of thyroid hormone may have adverse effects on cardiac function during this phase of recovery.	There is a need to evaluate the changes in levels of T3 following the first stage of reconstruction for hypoplastic left heart syndrome.
Plumpton et al	36 infants less than 12 months of age	2005	Increasing CPB time was associated with decreasing admission free T₃ and TSH. Younger and smaller infants had lower admission levels of free T₃.	Prospective studies of T₃ replacement in selected young infants (less than three months) with long CPB time (greater than 120 minutes) during congenital heart surgery are warranted.
Marks et al	21 patients, aged 1-11 years	2009	Alterations in illness severity preceded changes in thyroid function, with some of the biochemical changes not corrected by 8 days postoperatively. The degree of thyroid dysfunction was related to and predictive of clinical outcome and illness severity. CPB and aortic clamp times did not affect the degree of SES.	Thyroid function may be used as a marker of clinical status and as a predictor of outcome in this patient population.
Talwar et al	100 patients were randomized into 2 groups: 50 in the thyroxin group and 50 in the placebo group	2012	Low levels of T₄ were correlated with a greater postoperative morbidity, a prolonged postoperative course, prolonged mechanical ventilation, and increased inotropic requirements following CPB. There was a difference in levels of T₄ between the survivors and nonsurvivors	Prophylactic administration of total T4 for improving outcomes needs to be studied further.
Kornelius et al	19,642 cases and 78,568 matched controls	2015	ICM exposure was associated with higher risk of thyroid dysfunction, including hyperthyroidism and hypothyroidism.	Although ICM-related imaging and interventional studies improve the disease diagnosis rate and quality of health, physicians should be aware of the complications of ICM and should apply it cautiously in clinical practice.
Thaker/Levine et al	183 infants	2017	Hypothyroidism was diagnosed in 25% of infants with CHD after iodine exposure.	In neonates with CHD and impaired renal function exposed to excess iodine and multiple procedures, routine monitoring of thyroid function is warranted. Future studies should examine the association between hypothyroidism and neurocognitive function in this population.

Abbreviations: CHD, congenital heart defect; CPB, cardiopulmonary bypass; ICM, iodinated contrast media; SES, sick euthyroid syndrome; T₃, triiodothyronine; T₄, thyroxin; TSH, thyroid-stimulating hormone.

Treatment

Based on the pharmacological profile of thyroid hormones, it has been postulated that thyroid hormone replacement in infants may reduce postoperative morbidity and mortality. Therapy with T₃ has been suggested by many authors, but it is controversial.⁹ At present, existing studies on treating SES in children have had relatively small patient numbers as well as age, thereby limiting the ability to determine significant clinical effects.⁹ Overall, studies of prophylactic thyroid hormone replacement in preterm newborns do not support the use of prophylactic thyroid hormones to reduce neonatal mortality and morbidity or improve neurodevelopmental outcomes, but further studies focusing on infants with congenital heart defects are needed.²

In SES-1 and SES-2, additional tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone, and replacement of T₃ can reverse these findings. Triiodothyronine administration is associated with improved hemodynamics, reduced peripheral vascular resistance, increased cardiac output, and other effects, suggesting the potential utility of thyroid hormone replacement.⁹ Mullis-Jansson and colleagues showed that parenteral T₃ led to an improved postoperative function, reduced the need for inotropic agents and mechanical devices, decreased the incidence of myocardial ischemia, and decreased the incidence of atrial fibrillation and pacemaker therapy.²⁵ Bialkowsky showed a beneficial effect of T₃ supplementation after CPB in children, including a significant vasodilatation.²⁶ Chowdhury and colleagues initially reported a case series in which T₃ treatment decreased the systemic vascular resistance by more than 25%, increased cardiac output by more than 20%, resolved the existing metabolic acidosis, and reverted junctional rhythm to sinus rhythm.²⁷ Mackie and colleagues performed a randomized double-blind placebo-controlled trial of T₃ treatment in a selected group of 42 patients undergoing a Norwood procedure or a two-ventricle repair of interrupted aortic arch and ventricular septum defect. In this high-risk group of patients, T₃ supplementation proved to be safe and resulted in a higher systolic blood pressure and a more rapid achievement of negative fluid balance.²⁸ A more recent study by Chowdhury et al studied 28 patients with low serum total T₃ level; 14 patients were randomized to receive continuous T₃ infusion and this treatment resulted in a significantly lower inotropic requirement.²⁹ Also, of eight newborns tested, mixed venous oxygen saturation values showed a 17% increase in the T₃-treated group after 18 to 24 hours but only a 2% increase in the untreated group, although it did not reach statistical significance. The length of hospital stay and days of mechanical ventilation were not significantly different between the two groups. There were no adverse effects on blood pressure, heart rate, or cardiac rhythm in those treated with T₃.^2,30

The largest randomized clinical trial so far, which was conducted on 43 patients—The Triiodothyronine for Infants and Children Undergoing CPB (TRICC), focused on the administration of an injectable T₃ preparation in patients less than two years of age. The study demonstrated significant clinical advantages in patients younger than five months of age with a significant reduction in time to extubation, less use of inotropic support, and a better cardiac function. However, they showed an increase in time to extubation in those older than five months. This finding is consistent with the notion that younger patients with more complex operations and longer CPB times might benefit most from T₃ supplementation.^31,32 In 2000, Bettendorf et al, in a randomized double-blind study of 40 children, reported that those who received T₃ had a better left ventricular systolic function and cardiac index, but there was no statistically significant difference in intensive care time or mechanical ventilation support compared to children who did not receive T₃.³³ However, there was a much greater increase in cardiac function in the subgroup of patients given T₃ after a long operation or CPB. In a study by Portman et al, infants with either ventricular septal defect or tetralogy of Fallot repair who were given T₃ before the start of CPB and immediately after release of the aortic cross-clamp had a higher heart rate and blood pressure, without any other clinical changes.^34,35

In studies conducted among the adult population, Sirlak et al treated adult patients with low ejection fraction undergoing coronary artery bypass grafting with oral T₃ before and after surgery. They found that oral supplementation prevented the expected decline in thyroid hormone levels; they also found an improvement in left ventricular ejection fraction and a reduced use of inotropic drugs in the treatment group.^31,36 In a randomized placebo-controlled study, Klempherer et al found that after the administration of T₃ in 142 adult patients with coronary artery disease the clinical course remained unchanged.³⁴

In 2018, Talwar et al demonstrated that oral T₄ supplementation improves the cardiac index and reduces the inotropic requirement. In addition, it reduces the duration of mechanical ventilation, ICU and hospital stay, and therapeutic intervention scoring system in infants after surgery for complex congenital heart defects.³⁷

Toscano et al showed that there weren’t any abnormalities in myocardial structure or function in children with Down syndrome and subclinical hypothyroidism.³⁸ They suggested that thyroid function and health status should be monitored carefully, and l-thyroxine treatment should only be started when clinical signs and symptoms of hormone deficiency have clearly been shown.⁷

Passeri et al found that a rise in TSH levels was correlated with a marker of ventricular dysfunction. This supports the idea that even mild hypothyroidism may negatively affect the outcome of CHD children, which might be a further validation to support the benefit of replacement therapy.⁵

Finally, a recent case series of six postcardiac surgery pediatric patients with low serum T₃ levels showed that the single most important benefit observed was the conversion to sinus rhythm within 24 hours of T₃ administration. In three patients, the cardiac output increased by more than 50% and systemic vascular resistance decreased by 25%. Urine output increased by 50% in all patients, resolution of metabolic acidosis was seen in four patients, and a reduction in additional inotropic support of up to 50% was reported. No side effects of treatment were documented in this series.²¹

The acute application of thyroid hormone may have unexpected side effects based on the physiological profile of the hormones. Supplementation may aggravate a reduction in TSH secretion that may prolong the duration of transient hypothyroidism.²¹ Disadvantages of attempting to restore T₃ cellular levels may be alternations in calcium physiology.¹ Subclinical thyrotoxicosis may be associated with changes in cardiac performance and morphology; these may include increased heart rate, increased left ventricular mass index, increased cardiac contractility, diastolic dysfunction, and the induction of ectopic atrial beats or arrhythmias.⁹

The main finding from the Cochrane review of thyroid hormone supplementation for infants undergoing cardiac surgery is the lack of evidence from randomized trials as to whether thyroid hormone therapy is beneficial or harmful in infants up to one year of age.²¹ Studies evaluating thyroid hormone treatment in pediatric cardiac patients are summarized in Table 3.

Table 3.

List of Studies Evaluating Thyroid Hormone Treatment in Pediatric Cardiac Patients.

Study	Population	Year	Major Findings	Recommendations
Haas et al	Clinical review Review the actual literature on the development of SES in children after cardiac surgery—multiple age groups including preterms, neonates, and children	2006	Parenteral T₃ leads to an improved postoperative function, reduced the need for inotropic agents and mechanical devices, decreased the incidence of myocardial ischemia, and decreased the incidence of atrial fibrillation and pacemaker therapy. There is a beneficial effect of T₃ supplementation after CPB in children, including a significant vasodilatation. In this high-risk group of patients, T₃ supplementation proved to be safe and to increase cardiac output.	Children after cardiac surgery are at specific risk to develop a clinically important SES perioperatively. Despite clear evidence from the studies available, the demonstrated beneficial effects and the clear lack of negative effects make the prophylactic supplementation of T₃ a desirable treatment option, especially in high-risk groups. The administration of T3 to adults and children of various ages after cardiac surgery as well as in various other conditions of critical illness proved to be safe and well tolerated; no side effects have been demonstrated so far.
Chowdhury, et al	Review 75 consecutive patients of either sex undergoing cardiac surgery between the ages of birth and 18 years	2001	The fall in serum T3 is greater in patients undergoing complex cardiac surgical procedures. In the present study, T₃ treatment was accomplished safely with no untoward changes in blood pressure, heart rate, or cardiac rhythm.	There is a therapeutic benefit of T3 in the postoperative period by using a continuous infusion protocol to normalize serum T3 levels in newborn patients undergoing operations for complex congenital heart disease. A prospective randomized study of greater statistical power will be required to confirm these results.
Bettendorf et al (Cochrane review)	Triiodothyronine treatment in children after cardiac surgery: a double-blind, randomized, placebo-controlled study	2000	Better left ventricular systolic function and cardiac index, but there was no statistically significant difference in intensive care time or mechanical ventilation support compared to children who did not receive T₃.	Treatment of children with T₃ after cardiopulmonary bypass operations raises T₃ plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, T₃ reduces the need for postoperative intensive care
Portman et al (TRICC study)	A prospective, multicenter, double-blind, randomized, placebo-controlled trial to evaluate the effects of T₃ supplementation after CPB in children younger than age 2 years	2011	Time to extubation among children younger than 5 months of age recovering from cardiac surgery was reduced by T₃ supplementation during and after cardiopulmonary bypass. The clinical response was accompanied by an improvement in cardiac function and a decrease in inotropic support	The results of this study emphasize the importance of appropriate age or diagnostic stratification in this population. The data in this study are limited by lack of previous specification in age stratification. However, the data strongly support performance of another trial in the patients younger than 5 months of age.
Talwar et al	100 patients were randomized into 2 groups: 50 in the T₄ group and 50 in the placebo group	2018	Oral T₄ supplementation improves the CI and reduces the inotropic requirement. In addition, it reduces the duration of mechanical ventilation, ICU and hospital stay, and therapeutic intervention scoring system in infants after surgery for complex congenital heart defects.	Oral administration of T₄ is more efficacious in the complex group of patients but is probably not needed in the simple group. Although a matter of speculation, relatively shorter ventilation times with less need for inotropes and manpower needs could explain this difference in the simple group.
Toscano et al	305 patients with DS (157 girls, 148 boys) were followed up for a median of 39 months	2003	The study shows the absence of abnormalities of myocardial structure and function in children with Down syndrome and subclinical hypothyroidism.	Suggesting that thyroid function and health status should be monitored carefully and T₄ treatment only given when clinical signs and symptoms of hormone deficiency have been clearly shown. We also suggest that the use of load independent indexes is mandatory to warrant an adequate LV functional analysis.
Passeri et al	324 children (164 males, 160 females, aged 0.2-15.4 years) with CHD	2015	Reversal of hypothyroidism has been frequently observed in children. Even mild hypothyroidism may negatively affect the outcome of CHD children.	There is a need for further validation to support the benefit of replacement therapy. They propose the systematic TSH determination for the early diagnosis of primary hypothyroidism in CHD children.
Cochran review	Review Review of trials using random allocation to perioperative thyroid hormone therapy (supplementation or replacement) compared to control (placebo or no therapy) in infants (birth to one year of age) undergoing cardiac surgery requiring cardiopulmonary bypass	2004	There is a lack of evidence from randomized trials concerning the benefits and risks of T₃ supplementation in perioperative cardiac surgery for infants.	Further randomized controlled trials which include sufficiently large patients numbers in a variety of different age strata (neonates, infants, and older children) need to be undertaken. The studies will also need to examine whether thyroid hormone should be used prophylactically for all patients undergoing cardiac surgery or therapeutically once the patient demonstrates low serum thyroid hormone levels. Efficacy of this treatment should be assessed in terms of effects on specific cardiac parameters, postoperative morbidity and mortality, and neurodevelopment.

Abbreviations: CHD, congenital heart defect; CI, cardiac index; CPB, cardiopulmonary bypass; DS, Down syndrome; ICM, iodinated contrast media; ICU, intensive care unit; LV, left ventricular; SES, sick euthyroid syndrome; T₃, triiodothyronine; T₄, thyroxin; TRICC study, The Triiodothyronine for Infants and Children Undergoing Cardiopulmonary Bypass study; TSH, thyroid-stimulating hormone.

Searching ClinicalTrials.gov, a database of privately and publicly funded clinical studies conducted around the world and runs by the National Institute of Health and the US National Library of Medicine (https://clinicaltrials.gov/), revealed two ongoing trials: “Evaluation of thyroid exposure to radiation doses during pediatric cardiac catheterization performed for diagnosis or the treatment of congenital heart disease,” (NCT01693796) which was completed in 2015 but its results have not been published yet, and “Hypothyroidism with congenital heart diseases (CHD)” (NCT03496363), which is not yet recruiting and aiming at assessing the thyroid function in children with CHD from birth up to three years of age.

Summary

Pediatric patients with cardiac heart disease have high frequency of thyroid dysfunction. These patients might include children with genetic predisposition such as Down syndrome, congenital hypothyroidism, or preterm neonates with transient hypothyroidism. Furthermore, patients with CHD undergo many procedures including exposure to iodine or cardiac bypass, causing transient hypothyroidism or SES as described above.

In this population of infants who already bear a high risk of long-term developmental delay, detection of hypothyroidism may be even more consequential. As many infants do not display typical signs or symptoms of hypothyroidism, the diagnoses might be easily missed in those with transient hypothyroidism or delayed in the case with severe hypothyroidism until the emergence of overt signs which are difficult to recognize in critically ill infants. Serial monitoring of thyroid function is not routinely performed in infants undergoing surgical procedures and radiological procedures, and routine periodic monitoring of thyroid function may be necessary to reduce the risk of neurodevelopmental disabilities.⁸ There is currently insufficient evidence to advocate thyroid hormone supplementation for the prevention of postoperative morbidity and mortality in infants who undergo CPB.²¹ Triiodothyronine intervention was found to be of most clinical benefit in infants who have low cardiac output via an enhancement in left ventricular performance, a significant decrease in systemic vascular resistance, and improved myocardial oxygen consumption. However, adequately powered studies are needed before a uniform recommendation can be made.

Until there are significant results, therapeutic decisions should be made based on individual circumstances, taking into account the severity of the thyroid deficiency, as well as the symptoms that might be attributable to thyroid dysfunction² (Figure 1). Future studies in children with congenital heart defect are therefore needed in order to investigate the optimal frequency and timing of screening, the association between the severity and duration of hypothyroidism and neurocognitive function, and the essentiality of treatment with thyroid supplementations.^6,34

Footnotes

Authors’ Note

Reut Kassif Lerner carried out the initial literature search and review, drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted. Noah Gruber reviewed and revised the manuscript and approved the final manuscript as submitted. Uri Pollak consulted on postoperative treatment, reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Reut Kassif Lerner, MD

Uri Pollak, MD

Abbreviations and Acronyms

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