A Life Without Lemons: A Case of Severe Pulmonary Arterial Hypertension Secondary to Vitamin C Deficiency in a Child With Autism Spectrum Disorder

Learning Points

• Pulmonary arterial hypertension (PAH) is a rare, serious, and reversible complication of vitamin C deficiency in children.

• Vitamin C deficiency, amongst other micronutrient deficiencies, is common in children with ASD due to restrictive dietary intake.

• In cases of PAH of unknown cause in paediatric patients, serum vitamin C testing should be considered, with vitamin C supplementation as indicated.

1. Introduction

Pulmonary arterial hypertension (PAH) is a rare but serious complication of vitamin C deficiency in children [1]. Several case reports document resolution of PH with administration of vitamin C in paediatric patients [1, 2, 3, 4]. Deficiency of vitamin C, along with other micronutrients, is common in children with neuropsychiatric backgrounds due to restrictive dietary intake [5]. In this case report, we describe a case of PAH secondary to vitamin C deficiency in a child with autism spectrum disorder (ASD), without other clinical features of vitamin C deficiency. The PAH rapidly and completely resolved with vitamin C supplementation.

2. Case

An otherwise previously well 5‐year‐old boy with a background of non‐verbal ASD and mild viral induced wheeze was transferred to our tertiary centre from an outer‐metropolitan hospital for management of shock. He had a three‐day history of decreased oral intake and lethargy, with respiratory distress over the 24‐h prior to presentation. Inhaled Salbutamol was trialled at home, with subsequent collapse. No infective symptoms were present.

On arrival to our tertiary centre, physical examination was unremarkable other than tachycardia and tachypnoea, with no hypotension. There were no identified clinical features of scurvy such as joint swelling, corkscrew hairs, notable bruising or gingivitis. The venous blood gas revealed a metabolic acidosis (pH 7.14, bicarbonate 6 mmol/L, lactate 11 mmol/L), which was treated as possible sepsis with intravenous fluid boluses to a total of 40 mL/kg and intravenous antibiotics. No clinical improvement was observed; however, mild correction of the acidosis was demonstrated on repeat venous blood gas (pH 7.31, bicarbonate 9 mmol/L, lactate 5.6 mmol/L).

Despite aggressive fluid management, our patient remained tachycardic and developed cardiogenic shock (blood pressure 68/50 mmHg). An echocardiogram showed a severely dilated right atrium (RA) and right ventricle (RV) with severely impaired systolic function (fractional area change 26%, normal > 35%) and an estimated systolic pulmonary arterial pressure (PAp) of 59 mmHg (+ right atrial pressure [RAp]) based on the tricuspid regurgitation jet velocity (Figure 1). This reduced to 23 mmHg (+RAp) upon trial of 20 ppm of inhaled nitric oxide (iNO). Our patient's cardiac anatomy was otherwise normal with normal left ventricular systolic function. Given the response to iNO, intravenous sildenafil was commenced.

FIGURE 1.

A four‐chamber echocardiogram image during the acute presentation (A), showing marked dilatation of the right atrium (RA) and right ventricle (RV) with severe RV systolic dysfunction. Following vitamin C replacement and stabilisation on pulmonary vasodilator therapy, the echocardiogram normalised (B) with no persistent RA or RV dilatation, and normal RV systolic function.

Diagnostic investigations for PAH yielded an unremarkable full blood count, inflammatory markers, coagulation studies, electrolytes and renal function, thyroid function, liver function, thrombophilia screen, connective tissue disease panel, urine toxicology and metabolic screens, and chest radiograph. Troponin I and serum N‐terminal pro‐B‐type natriuretic peptide were elevated at 91 and 5390 ng/L respectively. A 12‐lead electrocardiogram suggested right ventricular strain. Blood and urine cultures were negative.

Chest computed tomography showed features of PAH with smooth interlobar septal thickening, parenchymal mosaicism and pleural effusions, raising concern for veno‐occlusive disease; however, this diagnosis was clinically inconsistent with the patient's improvement with iNO. No pulmonary embolism or left heart obstructive lesion was seen. Rapid trio whole genome sequencing did not identify any genetic variants of interest. Lung biopsy and diagnostic catheterisation were not undertaken due to their risk/benefit profiles.

Several attempts to wean the iNO were unsuccessful, with declining oxygen saturations and mean arterial pressure seen clinically, and worsening of right ventricular dilatation, systolic function, and estimated PAp evident on echocardiography. Following optimisation of sildenafil, bosentan was commenced and a trial of high dose vitamin C supplementation (250 mg orally daily) was undertaken.

An echocardiogram 3 days following vitamin C commencement demonstrated normalisation of the RA and RV size, RV systolic function and systolic PAp (19 mmHg + RAp) (Figure 1). The iNO was completely weaned after 4 days of vitamin C supplementation. A baseline vitamin C level of 0.6 mg/L (normal range 4–14 mg/L) was returned 1 week later, with deficiencies in vitamin B1, iron and folate also identified. A dietician review was undertaken, identifying a history of severely restrictive dietary intake prior to admission, and appropriate supplementation commenced.

Vitamin C supplementation was continued at discharge from hospital and is ongoing. Sildenafil and bosentan were weaned and ceased 3 weeks and 5 weeks post‐discharge respectively with serial echocardiography demonstrating consistently normal appearances. An echocardiogram 3 months' following the initial presentation showed normal RA and RV size, normal RV systolic function and no evidence of pulmonary hypertension.

3. Discussion

This report describes a rare case of PAH associated with vitamin C deficiency in a child with ASD. There was complete clinical and echocardiographic resolution of PAH following administration of vitamin C. Interestingly, this patient had no clinical features of vitamin C deficiency.

Awareness of Vitamin C deficiency as a cause for PAH has recently increased. A systematic review of case reports by Hemila and de Man in 2024¹ described 32 documented cases of vitamin C deficiency causing PAH, 13 of which were in children younger than 16 years of age [1, 2, 3, 4]. Half of these had a neuropsychiatric background. Right ventricular enlargement was reported in 24 of the 32 cases. For cases where PAp was available, there was a 2.4‐fold difference in median PAp prior to and following treatment with vitamin C [1]. Serum vitamin C testing—and a trial of vitamin C supplementation prior to the results becoming available should be strongly considered in children with PAH of unknown cause. The limited availability of vitamin C testing outside major centres and the time to receive a result support a trial of this well‐tolerated, affordable treatment that may result in complete reversal of PAH.

Whilst the academic literature on vitamin C deficiency‐related PAH is limited, historical records show that a correlation between scurvy and heart disease is not a novel finding. In his extensive research on scurvy and its history, Alfred J. Hess cites numerous autopsy reports dating back to the eighteenth century noting severe cardiomegaly in patients following sudden death while afflicted by scurvy [6].

In addition to its well‐known role in collagen synthesis, vitamin C is involved in many biochemical processes, including the amidation of several peptide hormones; the synthesis of nitric oxide, norepinephrine and carnitine; and the modulation of gene expression through epigenetic mechanisms [7]. Several mechanisms have been proposed for the correlation between vitamin C deficiency and PAH [1, 8]. Firstly, vitamin C increases the synthesis of nitric oxide in the endothelium by degrading asymmetric dimethyl L‐arginine, an endothelial nitric oxide synthase inhibitor [1, 8]. Nitric Oxide induces pulmonary vasodilation by increasing cyclic guanosine monophosphate (cGMP) within the pulmonary arterial smooth muscle cells, resulting in relaxation via cGMP‐dependent protein kinase activation, reducing pulmonary vascular resistance [1, 8]. Secondly, vitamin C acts as a cofactor of prolyl hydroxylase, which regulates hypoxia‐inducible factor‐1‐alpha (HIF‐1α) [9]. Low vitamin C, therefore, leads to increased HIF‐1α levels, similar to those seen in hypoxia. The result is an increase in angiogenesis, greater production of vasoconstrictor factors, and unregulated HIF‐mediated pulmonary vasoconstriction and subsequent reversible PAH development [1, 8, 9]. Finally, vitamin C is an antioxidant involved in the scavenging of reactive oxygen species, which are recognised contributors to the development of PAH [10].

Vitamin C deficiency, amongst other micronutrient deficiencies, is significantly more common in children with ASD than children with neurotypical development due to restrictive dietary intake [5]. This highlights the necessity for a multidisciplinary approach to health care for children with neuropsychiatric disorders, in order to prevent acute and chronic health complications and optimise patient outcomes.

4. Conclusion

We present a rare case of reversible, severe PAH associated with vitamin C deficiency in a child with non‐verbal ASD and restrictive feeding behaviours. We propose that in cases of PAH without clear cause, a serum vitamin C level should be sent and an early trial of vitamin C supplementation strongly considered. Additionally, a multidisciplinary approach regarding dietary intake should be taken in children with neuropsychiatric disorders to prevent acute and chronic health complications and achieve optimal patient outcomes.

Funding

The authors have nothing to report.

Ethics Statement

The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the Human Research Ethics Committee of Western Australia (HREC WA). As per the institutional and national guidelines, this case report did not require formal ethics committee review, and parent consent was obtained. All procedures involving human participants were conducted in accordance with the ethical standards of the institution and with the Declaration of Helsinki (1964), as revised in 2013.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.