Preterm heart failure and refractory lactic acidosis caused by congenital hypothyroidism: A case report and review of literature

Abstract

BACKGROUND

Congenital hypothyroidism (CH) is a common condition in both preterm and term infants characterized by either thyroid gland absence or hypofunctionality. The clinical association of refractory lactic acidosis and heart failure has rarely been observed in cases of pediatric patients with CH pathology. Here, we explored the etiological relationship between CH, heart failure, and refractory lactic acidosis to reflect the importance of thyroid function screening in neonates with heart disease.

CASE SUMMARY

A 33-day-old extremely premature female infant presented with tachypnea, respiratory distress, recurrent infections, and abdominal distension postnatal. On admission to our facility, she had cardiomegaly, hepatomegaly, and lactic acidosis (revealed on blood gas analysis), with lactate progressively rising to 25 mmol/L. Chest radiographs showed pulmonary congestion, while echocardiography revealed cardiac enlargement, left ventricular wall thickening, and pericardial effusion. Initial management aimed at correcting acidosis and treating heart failure proved ineffective. After reassessment, thyroid function tests showed significantly decreased triiodothyronine, free triiodothyronine, thyroxine, and free thyroxine levels, with a significantly increased thyroid-stimulating hormone level, confirming a CH diagnosis. Levothyroxine was administered, resulting in rapid correction of lactic acidosis and gradual improvement of thyroid function and systemic symptoms, culminating in full recovery and discharge. We also reviewed the relevant literature on thyroid and cardiac dysfunctions in order to explore their deeper association.

CONCLUSION

This case links CH-induced heart failure with refractory lactic acidosis, urging prompt thyroid screening in affected neonates to reduce mortality.

Key Words: Congenital hypothyroidism; Lactic acidosis; Heart failure; Neonate; Preterm; Case report

Core Tip: This report details a critical case of congenital hypothyroidism in a preterm infant, presenting as severe heart failure and refractory lactic acidosis. The infant showed a rapid, life-saving response to levothyroxine, highlighting congenital hypothyroidism’s role as a reversible cause of cardiovascular collapse. A key novelty is the profound lactic acidosis, a rarely reported feature of neonatal hypothyroidism. This case underscores the need for high clinical suspicion and repeat screening in preterm infants with unexplained heart failure or metabolic acidosis. Our findings advance understanding of thyroid hormones’ role in cardiac metabolism and confirm that prompt treatment is vital for excellent outcomes.

INTRODUCTION

Congenital hypothyroidism (CH) is one of the most common preventable causes of intellectual disability, with an estimated prevalence of 1 in 2000-3000 children[1], and an even higher rate among preterm infants[2]. Primary CH results from thyroid hormone deficiency due to thyroid gland agenesis, ectopia, or functional impairment. Its increased incidence in preterm infants is multifactorial, with proposed contributors including immature hypothalamic-pituitary-thyroid axis, medication exposure (including steroids, dopamine), non-thyroidal illnesses (such as respiratory distress syndrome), and iodine deficiency[3].

CH typically manifests with non-specific symptoms, including lethargy, feeding difficulties, prolonged jaundice, and abdominal distension, although some infants are asymptomatic at the time of diagnosis. The neurodevelopmental consequences of delayed diagnosis were well-established; however, the cardiovascular implications in neonates remain considerably underrecognized. In adults, hypothyroidism is closely related to heart failure and cardiac mortality[4]. However, reports of CH presenting with overt cardiovascular collapse and refractory lactic acidosis in early infancy are remarkably few. This case report details a 33-day-old preterm infant who developed severe heart failure and refractory lactic acidosis secondary to previously undiagnosed CH, demonstrating an exceptional response to levothyroxine (L-T4) replacement therapy.

CASE PRESENTATION

Chief complaints

A 33-day-old female infant was urgently transferred to our hospital for management of worsening respiratory distress and significant abdominal distension.

History of present illness

She was born prematurely at 27 weeks and 5 days of gestation via spontaneous vaginal delivery to a healthy 31-year-old mother, with a birth weight of 950 g. Her initial neonatal course was complicated by respiratory distress syndrome requiring intubation, surfactant administration, and subsequent transition to nasal continuous positive airway pressure support. She received standard prophylactic antibiotics (penicillin plus cefotaxime) for 48 hours in accordance with the expert consensus guidelines for neonatal sepsis[5], as well as intravenous caffeine citrate. Enteral feeding with breast milk was initiated on postnatal day 2. On day 18, her clinical condition deteriorated markedly, with the emergence of recurrent apneic episodes, decreased responsiveness, and progressive abdominal distension. Suspected late-onset sepsis prompted treatment with a 14-day course of meropenem, although blood cultures ultimately returned negative. By day 33, some clinical improvement was noted; however, the abdominal distension and respiratory distress persisted despite no radiological evidence of necrotizing enterocolitis.

History of past illness

The patient was a neonate with a medical history identical to that of the present case.

Personal and family history

Her mother had received a complete course of antenatal corticosteroids, and her prenatal examination showed no significant abnormalities. Her parents had no genetic or family history.

Physical examination

On admission, her physical examination revealed a poorly responsive infant with pallor and scattered ecchymosis. She exhibited severe respiratory distress with tachypnea (67 breaths/minute) and prominent intercostal, subxiphoid, and subcostal retractions. Cardiovascular examination revealed distant heart sounds with a continuous murmur audible along the left sternal border. Pulmonary auscultation revealed bilateral scattered rhonchi and moist rales. Abdominal examination showed significant distension with hepatomegaly palpable 3 cm below the right costal margin.

Laboratory examinations

Initial laboratory evaluation revealed the following: White blood cell count, 3.4 × 10⁹/L; neutrophils, 1.05 × 10⁹/L; hemoglobin, 69 g/L. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.204, bicarbonate 10.7 mmol/L) and a critically elevated lactate level (23 mmol/L). Myocardial enzymes were significantly elevated, with mild-to-moderate increases in certain metabolic markers, such as B-type natriuretic peptide and cardiac troponin I (Table 1).

Table 1 Changes in blood indexes before and after levothyroxine treatment during hospitalization.

Blood index (unit)	Before treatment	After treatment	Reference range
BNP (pg/mL)	3959.67	13.26	(0-100)
cTnI (μg/L)	0.484	0.047	(0-0.06)
CK-MB (μg/L)	77.67	8.85	(0-5)
CK (U/L)	1039	89	(39-192)
Ammonia (μmol/L)	99.9	34.5	(10-47)
Pyruvate (μmol/L)	240.7	79.9	(20-100)
β-hydroxybutyric acid (mmol/L)	0.78	0.15	(0-0.27)

BNP: B-type natriuretic peptide; cTnI: Cardiac troponin I; CK-MB: Creatine kinase-MB; CK: Creatine kinase.

Imaging examinations

Chest radiography revealed cardiomegaly and increased pulmonary congestion (Figure 1). Echocardiography showed cardiac enlargement, marked left ventricular wall thickening (Figure 2), a patent ductus arteriosus (PDA) measuring 4.5 mm in diameter, and pericardial effusion.

Figure 1 Chest radiography changes before and after levothyroxine treatment. A: Admission chest radiograph (2 days before levothyroxine) showed cardiomegaly and pulmonary congestion; B: Post-levothyroxine chest radiograph revealed marked improvement.

Figure 2 Cardiac color doppler ultrasound changes during levothyroxine treatment. A and B: Cardiac ultrasound (pre-levothyroxine and 2 days post-levothyroxine) revealed left ventricular hypertrophy and left heart enlargement (orange arrows); C and D: Ultrasound (29 days post-levothyroxine) showed improvement in left heart size and left ventricular hypertrophy (orange arrows); E and F: Ultrasound (92 days post-levothyroxine) showed normalized cardiac structure (orange arrows).

FINAL DIAGNOSIS

The infant was initially diagnosed with neonatal severe pneumonia, respiratory failure, heart failure, lactic acidosis, neonatal anemia, suspected neonatal sepsis, bronchopulmonary dysplasia, extreme prematurity, and extremely low birth weight.

TREATMENT

Initial treatment

Treatment included invasive mechanical ventilation, aggressive sodium bicarbonate infusion for acidosis correction, broad-spectrum antibiotic therapy with cefoperazone-sulbactam, and hemodynamic support with dobutamine (10 μg/kg/minute) and norepinephrine (0.3-0.5 μg/kg/minute) infusions. Diuresis was induced with furosemide, and anemia was corrected with a packed red blood cell transfusion (20 mL/kg).

Reexamination

Despite comprehensive supportive measures, the lactic acidosis remained refractory to treatment. The infant developed Kussmaul respiration and exhibited cherry-red lips, indicating profound metabolic derangement. Serial blood gas analyses showed progressive clinical deterioration, with lactate levels rising to 25 mmol/L by the second hospital day (Figure 3). An extensive diagnostic evaluation was initiated to identify the etiology of the refractory lactic acidosis, including bacterial cultures, inflammatory markers, hepatic and renal function tests, and blood/urine tandem mass spectrometry, all of which remained within normal limits. Notably, the newborn screening (NBS) for thyroid-stimulating hormone (TSH) performed on postnatal day 7 had been reported as normal. Family history was negative for metabolic or thyroid disorders, and maternal thyroid function during pregnancy was documented as normal. Given the persistent abdominal distension and refractory clinical course, thyroid function tests were repeated. The results were unequivocal: Profoundly depressed triiodothyronine [0.49 nmol/L, reference range (the same below), 1.11-3.62 nmol/L], free triiodothyronine (2.15 pmol/L, 5.1-8.0 pmol/L), thyroxine (12.80 nmol/L, 77.4-171.57 nmol/L), and free thyroxine (FT4) (1.03 pmol/L, 12.26-21.67 pmol/L) levels, accompanied by markedly elevated TSH levels > 150.000 mIU/L (1.7-9.1 mIU/L).

Figure 3 Lactate and bicarbonate levels before and after levothyroxine treatment. Lactate levels rose progressively post-admission and declined following levothyroxine treatment. Bicarbonate levels trended inversely to lactate. L-T4: Levothyroxine; HCO₃^-: Bicarbonate.

Rediagnosis and retreatment

A diagnosis of CH was established. L-T4 replacement therapy was initiated immediately at 12.5 μg/kg/day, resulting in a rapid and dramatic clinical response.

OUTCOME AND FOLLOW-UP

Serum lactate levels decreased by 43.6% within 5 hours of the first L-T4 dose, with complete normalization achieved within 3 days (Figure 3). Bicarbonate levels improved correspondingly. The signs of heart failure and abdominal distension resolved markedly, with regression of hepatomegaly and resolution of peripheral edema. Follow-up echocardiography showed remarkable improvement in cardiac function and resolution of ventricular wall thickening.

The infant’s clinical course thereafter showed steady improvement. Neuroimaging at 38 weeks postmenstrual age revealed normal findings. She was successfully weaned to room air and achieved full enteral feeding. She was discharged 57 days after admission, at the postmenstrual age of 40 weeks and 4 days, with continued L-T4 therapy. Careful endocrine follow-up with dose titration maintained euthyroidism until drug discontinuation at 3 years of age (Table 2). Subsequent monitoring until 4 years of age showed normalized cardiac findings and appropriate neurodevelopment with catch-up growth. Genetic evaluation and thyroid ultrasound revealed no abnormalities.

Table 2 Changes in thyroid function tests and levothyroxine dosage.

Age	T4 (nmol/L)	FT4 (pmol/L)	TSH (mIU/L)	TGAb (U/mL)	TPOAb (U/mL)	Dosage of L-T4
35 days	12.80	1.03	> 150.000	NE	NE	12.5 μg/kg/day
47 days	220.30	31.85	1.433	< 15.0	165.3	8 μg/kg/day
73 days	134.10	22.65	0.703	< 15.0	109.3	4.77 μg/kg/day
4 months	116.00	16.87	5.099	NE	NE	3.02 μg/kg/day
6 months	129.20	16.83	2.556	NE	NE	1.89 μg/kg/day
9 months	141.30	18.60	2.371	NE	NE	1.85 μg/kg/day
12 months	99.60	18.35	2.830	NE	NE	1.62 μg/kg/day
18 months	111.2	21.01	5.104	NE	NE	12.5 μg qod
27 months	113.7	17.61	4.884	NE	NE	12.5 μg every 2 days
36 months	105.0	16.83	4.657	NE	NE	Stop
37 months	119.8	20.88	4.080	NE	NE	Stop
Reference range	77.4-171.57	12.26-21.67	1.7-9.1	< 60	< 60

T4: Thyroxine; FT4: Free thyroxine; TSH: Thyroid-stimulating hormone; TGAb: Thyroglobulin antibody; TPOAb: Thyroid peroxidase antibody; L-T4: Levothyroxine; NE: No mention.

DISCUSSION

In newborns and infants, severe lactic acidosis usually results from severe hypoxia, infection, shock, heart failure, or inborn errors of metabolism such as pyruvate carboxylase deficiency[6] or mitochondrial disorders[7]. In this case, the infant had no family history of inborn metabolism errors, and no obvious abnormalities were found in bacterial cultures, inflammatory markers, hepatic and renal function, or blood and urine tandem mass spectrometry. The refractory nature of the lactic acidosis, unresponsive to conventional therapies, highlights the primacy of thyroid hormone deficiency in this clinical presentation. The immediate and definitive resolution following L-T4 administration establishes a clear dose-effect causal relationship. Therefore, the most likely cause was heart failure and metabolic dysfunction from CH. This case exemplifies a severe, life-threatening presentation of CH, including profound cardiovascular and metabolic compromise.

Thyroid hormone receptors are extensively distributed throughout myocardial tissue and cardiac endothelial cells. Thyroid hormone reduces systemic vascular resistance while increasing heart rate, contractile force, and cardiac output[8]. Therefore, hypothyroidism can adversely affect heart muscle bioenergetics, leading to myocardial injury and dysfunction that progresses to heart failure[9], with consequent lactate overproduction. Even subclinical hypothyroidism is linked to cardiovascular risk in younger populations[10], potentially through mechanisms such as left ventricular diastolic dysfunction from endothelial dysfunction, arterial stiffness, and inflammatory state which are mediated by TSH apoptosis-derived microparticles, as well as systolic dysfunction from cardiac remodelling and increased predisposition to heart failure[11]. In this case, the infant developed heart failure and left ventricular posterior wall thickening due to hypothyroidism. L-T4 therapy rapidly normalized thyroid function and biomarkers (B-type natriuretic peptide, cardiac troponin I, lactate), and gradually reversed the structural cardiac changes. This highlights hypothyroidism as an important etiological factor of cardiomyocyte remodeling and heart failure in early infancy.

A proven link exists between hypothyroidism and both heart failure and cardiac mortality. However, CH-induced severe heart failure with refractory lactic acidosis is rarely reported in extremely preterm infants and can be easily misdiagnosed owing to frequent complications. One such complication is hemodynamically significant PDA, which can also cause heart failure. In this case, echocardiography revealed a PDA > 2 mm with left heart enlargement; however, typical hemodynamically significant PDA signs, such as widened pulse pressure, bounding pulses, or left atrial-to-aortic root ratio > 1.5, were absent[12]. Moreover, follow-up echocardiography still indicated a 3 mm PDA even after lactate had markedly decreased, indicating its minor role. Other potential factors included severe lung disease (infections, respiratory failure, and bronchodysplasia) and anemia. The infant had received prolonged invasive respiratory support and aggressive anti-infective therapy using cefoperazone-sulbactam; however, bacterial culture and inflammatory marker monitoring were both negative. The rapid decline in lactate levels shortly after L-T4 treatment is unlikely to be attributed to anti-infective therapy or respiratory support. While anemia was promptly corrected with transfusion, lactate continued rising over the following 2 days. Overall, the rapid response to L-T4 treatment indicates that hypothyroidism was the primary driver of the clinical presentation, with other factors playing relatively minor roles.

To better understand the clinical manifestations of the cardiac effects of hypothyroidism in children, we reviewed 21 previously reported cases of cardiac dysfunction directly or partly caused by hypothyroidism in children (Supplementary Table 1). Overall, these cases suggested that prognosis was generally good with timely treatment. In these cases, cardiac dysfunction caused by hypothyroidism was mainly manifested as pericardial effusion (7/21)[13-19]; arrhythmias (10/21), including bradycardia (5/10)[17,19-22], atrioventricular heart block (3/10)[20,23,24], long QT intervals (1/10)[25], and refractory torsades de pointes (1/10)[26]; cardiogenic shock (4/21)[22,24,27,28]; heart failure (3/21)[29-31]; disproportionately thickened septum (1/21)[32]; hypertrabecular aspect of left ventricular myocardium (1/21)[25]; and perioperative cardiac arrest (1/21)[33]. Notably, refractory lactic acidosis, as seen in this case, has not been previously reported and appears extremely rare. With timely correction of thyroid function, most patients had a good prognosis and improved cardiac function. This highlights that hypothyroidism is an important and reversible differential diagnosis for cardiac dysfunction and refractory lactic acidosis.

Owing to the transplacental passage of maternal thyroid hormones, which provide protective effects for approximately 2 weeks after birth, only 1%-4% of infants with CH are detected by clinical examination at birth[8]. As neonatal manifestations are often subtle or atypical, most countries have established NBS programs to identify infants at high risk. However, a crucial aspect of this case, as evidenced by screening data over recent decades, involves the limitations of initial NBS in preterm infants, having increased risk for delayed TSH elevation, up to a maximum age of 56 days of life[2,3]. European guidelines (2021) recommend repeat screening at 10-14 days after birth for preterm infants[1], while current guidelines (2023) advise a second NBS at 2-4 weeks of age, even after a normal initial result, for neonates meeting any of the following criteria: Acute illness requiring admission; prematurity (< 32 weeks gestation); very low birth weight (< 1500 g); transfusion prior to the first NBS; monozygotic (or same-sex twin if zygosity is unknown) or multiple birth status; or trisomy 21. Given its considerably lower cost, repeat NBS is preferred over serum TSH and FT4 testing in these cases[34]. In addition, some centers perform a third screen at 6-8 weeks of age for extremely preterm infants to enhance detection, though this increases false-positive risks and costs[2]. A study of 5992 very preterm Chinese infants reported that dynamic thyroid function screening by weeks throughout the first month of life is crucial for the timely diagnosis and treatment of CH[35].

Additionally, research suggests that a lower TSH cut-off may be appropriate for second screenings, as preterm infants < 34 weeks more commonly exhibit blood TSH levels of 5-9.9 mIU/L than ≥ 10 mIU/L[36]. Some protocols employ a two-stage screen (TSH cut-off 8 mIU/L at 48-72 hours, then 6 mIU/L at 2 weeks)[2]. However, an Australian study reported that while a lower threshold (≥ 8 mIU/L) improved CH detection, it also increased recall rates eightfold[37]. In the present case, the primary focus on managing prematurity-related complications likely led to the omission of a repeat thyroid function test. This omission highlights the critical need for rigorous adherence to follow-up screening protocols[34], a trade-off that merits further clinical and economic evaluation.

The management of critically ill infants with CH necessitates aggressive hormone replacement. Current guidelines recommend that neonates diagnosed with CH through a second screening begin L-T4 treatment as soon as possible, and no later than 2 weeks after birth or immediately after confirmatory thyroid function testing, with the initial dose individualized based on TSH and FT4 levels[1]. The 2025 Chinese guidelines advise a full initial replacement L-T4 dose to rapidly normalize thyroid hormone levels within 2 weeks and TSH within 4 weeks. Specifically, the recommended initial dose for mild CH cases (FT4 > 10 pmol/L with elevated TSH) is 10 μg/kg/day, while 10-15 μg/kg/day for severe CH cases (FT4 < 5 pmol/L with elevated TSH)[38]. In this case, an initial L-T4 dose of 12.5 μg/kg/day was critical for rapidly reversing severe deficiency and cardiac dysfunction; however, it later led to elevated FT4 levels, necessitating careful follow-up and downward titration to prevent iatrogenic hyperthyroidism, a particular concern at L-T4 doses exceeding 10.2 μg/kg/day[39]. While overtreatment should be avoided, excessive caution should not lead to undertreatment, which may increase the risk of suboptimal neurodevelopmental outcomes. A balanced approach to dosing and vigilant monitoring is essential in optimizing outcomes for these infants.

However, causal inference in individual cases has inherent limitations. Furthermore, this atypical CH case, with normal initial TSH and ultrasound, presented diagnostic ambiguity. The long-term impact of our treatment on her neurological outcomes requires continued follow-up, with imaging and neurological assessments.

CONCLUSION

This case serves as an essential reminder to clinicians that CH can represent a reversible etiology of cardiovascular collapse in infants. In any infant, particularly those born preterm, presenting with unexplained heart failure, shock, or refractory lactic acidosis, thyroid function must be urgently evaluated regardless of previous NBS results. Prompt diagnosis and initiation of thyroxine replacement therapy can be life-saving and facilitate excellent cardiac and neurodevelopmental outcomes.

ACKNOWLEDGEMENTS

We would like to thank You Lu for collecting data.