Vitamin C Deficiency-Induced Pulmonary Arterial Hypertension

We report a case of a man in his 60s who developed pulmonary arterial hypertension (PAH) in association with profound vitamin C deficiency. Decreased availability of endothelial nitric oxide and activation of the hypoxia-inducible family of transcription factors, both consequences of vitamin C deficiency, are believed to be mechanisms contributing to the pathogenesis of the pulmonary hypertension. The PAH resolved following vitamin C supplementation. The current case highlights the importance of testing for vitamin C deficiency in patients with PAH in the proper clinical setting. We report a case of a man in his 60s who developed pulmonary arterial hypertension (PAH) in association with profound vitamin C deficiency. Decreased availability of endothelial nitric oxide and activation of the hypoxia-inducible family of transcription factors, both consequences of vitamin C deficiency, are believed to be mechanisms contributing to the pathogenesis of the pulmonary hypertension. The PAH resolved following vitamin C supplementation. The current case highlights the importance of testing for vitamin C deficiency in patients with PAH in the proper clinical setting. A man in his 60s with a history of systemic hypertension and increasing dyspnea on exertion was referred to an outpatient pulmonary clinic for further evaluation of pulmonary hypertension. During a hospitalization for systemic hypertensive urgency, a transthoracic echocardiogram performed for increasing dyspnea revealed a mildly dilated right ventricle and an increased estimated pulmonary artery systolic pressure of 76 mm Hg (Fig 1, Video 1). He also had lower extremity swelling and rash along with joint pain in his hips, knees, and feet for the past 4 months. Further questioning revealed that his diet consisted mainly of candy and sports drinks. The patient’s physical examination was notable for the following: gum hypertrophy; increased P2 on cardiac auscultation; bilateral symmetrical pitting edema; hair loss on extremities; and a diffuse, petechial lower extremity rash bilaterally from mid-calf down. His lungs were clear to auscultation, and no right ventricular heave or jugular venous distention was appreciated. The patient’s right heart catheterization revealed a pulmonary artery pressure of 72/22 mm Hg with a mean pressure of 41 mm Hg (Table 1). He had a normal pulmonary capillary wedge pressure and preserved right atrial pressure with a significant vasodilator response to inhaled nitric oxide. Autoimmune evaluation was negative. Results of a biopsy of the patient’s lower extremity rash showed mild vascular proliferation in the papillary dermis with perivascular hemosiderin deposition and perifollicular erythrocyte extravasation. Focal fat necrosis was seen with no evidence of vasculitis. These findings were suggestive of severe vitamin C deficiency; given the patient’s negative autoimmune evaluation, rheumatology did not believe his rash was vasculitic, and vascular surgery discounted venous disease. The patient had no medication exposure that would explain petechial rash or gum hypertrophy. He was subsequently found to have a vitamin C level < 0.1 mg/dL (0.2-2 mg/dL), hemoglobin level of 8.4 g/dL (13.5-16 g/dL), iron level of 22 μg/dL (49-181 μg/dL), and 25-OH-vitamin D level of 12 ng/mL (20-100 ng/mL). He was prescribed vitamin C 1 g bid and 1,000 units of vitamin D3 daily. Over 5 months, the patient’s lower extremity rash and swelling and dyspnea improved. His vitamin C level increased to 1.5 mg/dL, hemoglobin rose to 11.3 g/dL, and a repeat transthoracic echocardiogram revealed normal right ventricular size and function with a drop in estimated pulmonary artery systolic pressure to 29 mm Hg (Fig 2, Video 2).Table 1Data From the Study Patient’s Right Heart CatheterizationConditionRestAfter Inhaled Nitric Oxide 20 ppmHeart rate, beats/min7270Arterial pressure, mm Hg159/98…Arterial oxygen saturation (room air)99%99%RA oxygen saturation61%…PA oxygen saturation58%71%Cardiac output (thermodilution), L/min3.54.3Cardiac index, L/min/m22.22.7Mean RA pressure, mm Hg5…PA pressure (systolic/diastolic), mean, mm Hg72/22 (41)47/13 (28)Mean PA wedge, mm Hg1111Pulmonary vascular resistance, dyn · s/cm5694316PA = pulmonary artery; ppm = parts per million; RA = right atrial. Open table in a new tab PA = pulmonary artery; ppm = parts per million; RA = right atrial. The current case illustrates the potential contribution of dietary vitamin C deficiency to the development of PAH. The patient had a history of several months of malnourishment associated with weight loss, a virtually undetectable vitamin C level, and a right heart catheterization documenting the presence of moderate PAH. PAH resolved following repletion of vitamin C, suggesting vitamin C deficiency as the major cause of PAH. To the best of our knowledge, there are only a few previously reported cases of vitamin C deficiency-induced PAH in the adult population. This case is unique in that the patient’s PAH resolved with vitamin C supplementation alone without iron supplementation or PAH-specific treatment; in the other cases, the latter two therapies were used.1Kupari M. Rapola J. Reversible pulmonary hypertension associated with vitamin C deficiency.Chest. 2012; 142: 225-227Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 2Marston N.A. Penn E. Olenchock B.A. Abstract 14894: a shocking deficiency: an unusual case of rapidly progressive pulmonary hypertension.Circulation. 2018; 136A14894Google Scholar Vitamin C deficiency is defined as a serum concentration < 0.2 mg/dL, and it occurs when vitamin C intake is below a critical amount (10 mg/d) for a prolonged period. It is associated with features of scurvy, which include failed wound healing, petechial hemorrhages, follicular hyperkeratosis, gum hypertrophy, and bleeding.3Schleicher R.L. Carroll M.D. Ford E.S. Lacher D.A. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES).Am J Clin Nutr. 2009; 90: 1252-1263Crossref PubMed Scopus (324) Google Scholar Vitamin C is a multipotent substance integral to the hydroxylation of proline and lysine, which is essential to collagen synthesis and connective tissue integrity. Vitamin C also acts to increase the content of endothelial cell tetrahydrobiopterin, which increases the activity of nitric oxide synthase, a function vital to healthy endothelial function.4Huang A. Vita J.A. Venema R.C. Keaney Jr., J.F. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin.J Biol Chem. 2000; 275: 17399-17406Crossref PubMed Scopus (308) Google Scholar, 5Suzuki Y.J. Steinhorn R.H. Gladwin M.T. Antioxidant therapy for the treatment of pulmonary hypertension.Antioxid Redox Signal. 2013; 18: 1723-1726Crossref PubMed Scopus (16) Google Scholar Both iron and vitamin C stimulate hypoxia-inducible family hydroxylases; deficiency of either leads to upregulation of hypoxia-inducible family transcription factors and critical oxidase enzymes, which in turn promotes endothelial dysfunction that predisposes to PAH.6Smith T.G. Robbins P.A. Ratcliffe P.J. The human side of hypoxia-inducible factor.Br J Haematol. 2008; 141: 325-334Crossref PubMed Scopus (210) Google Scholar, 7Humbert M. Morrell N.W. Archer S.L. et al.Cellular and molecular pathobiology of pulmonary arterial hypertension.J Am Coll Cardiol. 2004; 43: 13S-24SCrossref PubMed Scopus (1287) Google Scholar, 8Kaelin Jr., W.G. Ratcliffe P.J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.Mol Cell. 2008; 30: 393-402Abstract Full Text Full Text PDF PubMed Scopus (2203) Google Scholar In this regard, it is remarkable that in the study patient, vitamin C supplementation alone, without iron supplementation, was associated with reversal of PAH. Accordingly, vitamin C may alleviate some of the effects of iron deficiency as well. Vitamin C is needed for dietary absorption of iron as well as for maximal uptake of iron from transferrin, the sole source of iron for erythropoiesis.9Lane D.J. Jansson P.J. Richardson D.R. Bonnie and Clyde: vitamin C and iron are partners in crime in iron deficiency anaemia and its potential role in the elderly.Aging (Albany NY). 2016; 8: 1150-1152Crossref PubMed Scopus (14) Google Scholar Experimental animal models have shown the effectiveness of vitamin C and other antioxidants in blunting PAH development and progression, but these factors have not been adequately studied in humans.10Xiang R.P. Sun W.D. Wang J.Y. Wang X.L. Effect of vitamin C on pulmonary hypertension and muscularisation of pulmonary arterioles in broilers.Br Poult Sci. 2002; 43: 705-712Crossref PubMed Scopus (45) Google Scholar The current case highlights the importance of checking vitamin C levels in patients with PAH at risk for vitamin C deficiency, as well as the potential therapeutic role of vitamin C supplementation in patients who are deficient. Whether vitamin C supplementation, as with iron supplementation,5Suzuki Y.J. Steinhorn R.H. Gladwin M.T. Antioxidant therapy for the treatment of pulmonary hypertension.Antioxid Redox Signal. 2013; 18: 1723-1726Crossref PubMed Scopus (16) Google Scholar, 11Ruiter G. Manders E. Happé C.M. et al.Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency.Pulm Circ. 2015; 5: 466-472Crossref PubMed Scopus (67) Google Scholar could be helpful in a broader population of patients with PAH remains to be determined. 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