Scurvy-induced pulmonary arterial hypertension

Discussion

PAH includes idiopathic PAH, drug/toxin-mediated PAH, heritable PAH as well as PH resulting from connective tissue disease, HIV infection, congenital heart disease with left-to-right shunting, schistosomiasis infection and portal hypertension. Two other rare forms of PAH include pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.1 The pathogenesis of PAH is a proliferative vasculopathy, characterised by vasoconstriction, cell proliferation, concentric medial hypertrophy, fibrosis and plexiform lesions with thrombosis in situ of the small pulmonary arteries and arterioles. Pathologic findings include hyperplasia and hypertrophy of all three layers of the vascular wall of the pulmonary arteries (intima, media, adventitia), resulting in severe loss of cross-sectional area and increased right ventricular afterload.1

Scurvy-induced PAH is thought to occur as a result of the loss of the vasodilatory effect of ascorbic acid, whereby vitamin C increases synthesis of endothelial NO in the pulmonary circulation.7 Moreover, both iron and vitamin C are cofactors for prolyl hydroxylase enzymes, which are responsible for regulating hypoxia-inducible transcription factors (HIFs).8 Vitamin C deficiency, thus, contributes to unregulated HIF-mediated pulmonary vasoconstriction and subsequent PAH development. PAH related to vitamin C deficiency is reversible; however, the lack of reported cases in the literature often results in delayed diagnosis and potentially fatal disease.

Metabolism of L-arginine by the enzyme NO synthase (NOS) results in formation of a powerful vasodilator; NO (figure 6). The presence of a low endothelial NO level has been associated with the development of PAH. The endothelial NOS (eNOS) is the predominant source of NO in the endothelial cells of the pulmonary vasculature. NO acts by increasing cyclic guanosine monophosphate (cGMP) within the pulmonary artery smooth muscle cells, causing relaxation through activation of cGMP-dependent protein kinase. Lung specimens from subjects with PAH show reduced or absent eNOS expression and higher levels of asymmetric dimethyl L-arginine (ADMA), an eNOS inhibitor.9 Ascorbic acid has been shown to increase NO production within the endothelium by degrading ADMA. Additionally, vitamin C stabilises and increases eNOS cofactor tetrahydrobiopterin while inhibiting the arginase pathway that competes for arginine. Thus, deficiency of ascorbic acid decreases NO levels with subsequent vasoconstriction and eventual proliferative vasculopathy with PVR and proliferation involving all three layers of the vessel wall. Another important mechanism involved in the pathogenesis of scurvy-related pulmonary arterial vasculopathy is the inappropriate activation of HIF in the absence of hypoxia, leading to an exaggerated pulmonary vasoconstrictive response.10

Vitamin C deficiency leading to PH has been reported in the medical literature, but it appears to be rare, or at least rarely recognised and reported. We present the results of a literature review of the topic, with the basic details of reported cases summarised in table 1.

Abbas et al 6 described the case of a 50-year-old woman presenting with heavy menses, ecchymosis, exertional dyspnoea and jaundice. She was subsequently diagnosed with PH due to poor diet. Vitamin C level was very low. She was started on ascorbic acid supplementation with subsequent clinical recovery. Her TTE was reported as normal at her subsequent 4-week follow-up visit.

Ghulam Ali and Pepi11 described a 48-year-old woman with ecchymosis, exertional dyspnoea and oral ulceration. She underwent a TTE that suggested PH, which was confirmed by RHC. Shortly after admission, the patient’s condition deteriorated with development of severe cardiogenic shock after she was started on intravenous treprostinil. Additional history revealed that lettuce was the main component of her diet for the preceding year, leading to clinical suspicion for scurvy. Intravenous vitamin C supplementation was started with rapid clinical improvement after 36 hours. A repeat TTE 1 month later was normal.

Nagamatsu et al 12 described a 40-year-old woman who was admitted with ecchymosis, palpable purpura and dyspnoea. The patient was diagnosed with PH, which was confirmed on RHC. Epoprostenol infusion failed to significantly reduce the mean PAP. Further history revealed a very poor diet, and vitamin C level was undetectable. The patient was started on intravenous vitamin C supplementation as well as Sildenafil. Repeat TTE and RHC showed complete recovery.

Dean et al 13 described a 66-year-old man with coeliac disease presenting with progressive dyspnoea and ecchymosis. This patient was diagnosed with PH. Initially, he improved on diuretics and anticoagulation but was admitted a few months later with worsening symptoms. Repeat TTE revealed RVSP (right ventricular systolic pressure) of 80 mm Hg with no clinical improvement despite treatment with bosentan. During reassessment, the patient reported that his diet had been lacking fruits and vegetables for the past 8 months. Vitamin C level was undetectable, and he was started on vitamin C supplementation with clinical improvement, leading to a full recovery, as confirmed by a repeat TTE.

Nagamatsu et al 12 described a 73-year-old woman with a clinical presentation suggestive of scurvy in addition to exertional dyspnoea. In this case, the patient had severe PH on TTE. PAH was confirmed via RHC. A vasoreactivity test with adenosine infusion was positive. A detailed history revealed that the patient was sensitive to many foods, raising suspicion for scurvy-related PAH. Subsequent vitamin C level was undetectable, confirming the diagnosis. The patient was started on vitamin C therapy and nifedipine, and she reported complete recovery at 3-month follow-up, with a normal RVSP on TTE.

There has also been a reported case in the paediatric literature. Gayen et al 14 described a 6-year-old boy with a 3-month history of painful multifocal bone lesions who experienced cardiac arrest while undergoing bone marrow aspiration under sedation. The patient was successfully resuscitated but subsequently developed persistent tachycardia. TTE showed PH. Given PH and the bone lesions, ascorbic acid level was measured and found to be undetectable. Initially, he was given milrinone and inhaled NO, then switched to sildenafil and vitamin C. The patient underwent full recovery with a normal TTE at 4-week follow-up. It was hypothesised that his cardiac arrest was related to his previously undiagnosed PH.

Shah et al 15 described a 48-year-old woman developing rapidly progressive chest pain and shortness of breath. History revealed that during the past year, she also developed recurrent pericarditis, joint pain and a rash. Further investigation was undertaken and a TTE was done showing severe right ventricular dysfunction. RHC was done and showed elevated mean PAP of 41 mm Hg. Vasoreactivity testing was positive. The patient was started on epoprostenol, yet, continued to worsen clinically and had a persistently elevated PVR requiring vasopressors. Vitamin C levels were undetectable. The patient then disclosed that her diet consisted mainly of coffee, chocolate and iceberg lettuce. She started on oral vitamin C supplementation along with sildenafil therapy and showed a tremendous clinical improvement, along with normalisation of her vitamin C levels and TTE findings over the next 2 weeks.

Frank et al 16 reported a male patient in his 60s who was referred to an outpatient pulmonary clinic reporting of worsening exertional dyspnoea. During a hospitalisation for systemic hypertension, a TTE was done which showed mild right ventricular dilation. On further questioning, it was found that his diet mainly consisted of candy and sports drinks. RHC was done and showed an elevated mean PAP of 41 mm Hg. PAWP was normal and the pulmonary vessels showed strong response to vasodilator administration during catheterisation. Major causes of PH were excluded, biopsy of skin lesions showed findings supportive of vitamin C deficiency, which led to a vitamin C workup showing a level of less than 0.1 mg/dL. He was prescribed oral vitamins C and D daily. Over the next 5 months of therapy, his rash, joint pain, oedema and dyspnoea significantly improved. TTE was repeated and showed disappearance of right ventricular dilation and a significant drop of PASP. Notably, this case demonstrated how PAH was treated with vitamin C supplementation alone without iron supplementation or the use of PAH-specific therapy.

Azar et al 17 reported a 35-year-old woman presenting to the hospital with painful lower limb oedema, dyspnoea, gingival bleeding and ecchymosis that had progressively worsened over 6 months. Physical examination showed poor dental hygiene, corkscrew hair and crackles on the respiratory exam. Vasculitis was suspected and glucocorticoids were administered but therapy failed. Laboratory findings were significant for anaemia, thrombocytopenia and elevated BNP levels. Urine toxicology screen was positive for benzodiazepine and opioids. Given her physical examination and the history of drug abuse, a nutritional deficiency was suspected and she was started on empirical vitamin C supplementation. TTE revealed severe PAH. Vitamin C levels came back undetectable; the patient continued taking vitamin C supplementation and showed marked improvement. RHC done 2 weeks after discharge showed complete resolution of the PAH.

Frank et al 16 described a 17-year-old man who presented to the emergency department reporting of chest pain, leg pain and bruising without trauma. On further questioning, it was revealed that he had many episodes of gum bleeding and a poor diet. Physical examination showed a loud P2 along with symmetric bilateral pedal oedema and bilateral lower limb ecchymoses, petechiae and corkscrew hairs. TTE was done and showed evidence of PH with TR. Extensive work up was done revealing undetectable levels of vitamin C, along with low levels of iron and vitamin D. The patient was admitted and treated with vitamin C and D supplementation along with iron. Follow-up TTE 1 and 6 months after discharge showed complete resolution of PH and TR.

Finally, Azar et al,17 described a patient who presented with progressive exertional dyspnoea and signs of advanced right heart failure. The initial diagnostic workup did not reveal any significant findings. Her ECG showed right axis deviation, as well as RVH, right bundle branch block and right ventricular strain. The patient’s TTE showed a severely dilated right ventricle with moderately reduced function. Subsequent RHC confirmed the diagnosis of PAH, and shortly after admission, the patient developed severe cardiogenic shock refractory to maximal supportive management including pulmonary vasodilators. Laboratory data showed the patient’s ascorbic acid level as zero; however, she passed away before supplementation with vitamin C. This was the only reported case where the patient did not survive; in all other reviewed cases, patients showed complete recovery after appropriate treatment with vitamin C.