Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports

Abstract

Background: In the early literature, unintentional vitamin C deficiency in humans was associated with heart failure. Experimental vitamin C deficiency in guinea pigs caused enlargement of the heart. The purpose of this study was to collect and analyze case reports on vitamin C and pulmonary hypertension.

Methods: We searched Pubmed and Scopus for case studies in which vitamin C deficiency was considered to be the cause of pulmonary hypertension. We selected reports in which pulmonary hypertension was diagnosed by echocardiography or catheterization, for any age, sex, or dosage of vitamin C. We extracted quantitative data for our analysis. We used the mean pulmonary artery pressure (mPAP) as the outcome of primary interest.

Results: We identified 32 case reports, 21 of which were published in the last 5 years. Dyspnea was reported in 69%, edema in 53% and fatigue in 28% of the patients. Vitamin C plasma levels, measured in 27 cases, were undetectable in 24 and very low in 3 cases. Diet was poor in 30 cases and 17 cases had neuropsychiatric disorders. Right ventricular enlargement was reported in 24 cases. During periods of vitamin C deficiency, the median mPAP was 48 mmHg (range 29-77 mmHg; N = 28). After the start of vitamin C administration, the median mPAP was 20 mmHg (range 12-33 mmHg; N = 18). For the latter 18 cases, mPAP was 2.4-fold (median) higher during vitamin C deficiency. Pulmonary vascular resistance (PVR) during vitamin C deficiency was reported for 9 cases, ranging from 4.1 to 41 Wood units. PVR was 9-fold (median; N = 5) higher during vitamin C deficiency than during vitamin C administration. In 8 cases, there was direct evidence that the cases were pulmonary artery hypertension (PAH). Probably the majority of the remaining cases were also PAH.

Conclusions: The cases analyzed in our study indicate that pulmonary hypertension can be one explanation for the reported heart failure of scurvy patients in the early literature. It would seem sensible to measure plasma vitamin C levels of patients with PH and examine the effects of vitamin C administration.

Keywords: Antioxidants; Ascorbic acid; Case report; Heart failure; Oxidative stress; Pulmonary hypertension; Pulmonary vascular resistance; Scurvy; Systematic review.

Fig. 1

Mean pulmonary artery pressure (mPAP) during scurvy and after vitamin C administration. mPAP was available at baseline for 28 patients, but 1 patient died before vitamin C was given [78]. The median mPAP level was 47 mmHg during scurvy. mPAP level after vitamin C administration was available for 18 cases, with the median mPAP 20 mmHg. The lines indicate the patients with both values. The mPAP level during scurvy was 2.4 fold (median; range 1.2–4.1) higher than the level during vitamin C administration. The red dash line indicates 20 mmHg, which is the limit for concluding PH [33]

Fig. 2

Pulmonary vascular resistance (PVR) during scurvy and after vitamin C administration. PVR was available at the baseline for 9 cases, but 1 case died before vitamin C [78]. Follow-up PVR level was available for 5 cases with the lines showing the paired values. During scurvy, the PVR level was 9 times (median) as high as during vitamin C administration. The red dash line indicates 2 Wood units, which is the limit for concluding PAH [33]. See extracted data in Supplement 2

Fig. 3

Evolution of mPAP and TAPSE over time. mPAP is shown with filled circles on the left-hand side, and the TAPSE with open triangles on the right-hand side. Each point indicates one observation, and the lines are added to help visualize the change over time. Normal TAPSE ≥ 18 mm [33]. Note that the time scale of the horizontal axis is not constant. Time points ≤ 0 indicate the period during scurvy. Vitamin C administration was started soon after the time point 0. Data are for: (A) a 40-year-old male in France [80], (B) a 7-year-old boy in Malaysia [103], (C) a 2-year-old girl in Japan [95], (D) a 3-year-old boy in Japan [89], (E) a 40-year-old female in Finland [90], (F) a 17-year-old male in the USA [85], (G) a 6-year-old boy in the USA [98], (H) a 66-year-old male in Italy [87]. See extraction of data in Supplementary files 1 and 2. TAPSE, tricuspid annular plane systolic excursion

Fig. 4

Effect of vitamin C on LV eccentricity index in pulmonary hypertension patients. Normal LV eccentricity index is 1.0 [33, 109]. Each point indicates an observation, and the lines are added to help visualize the change over time. Time point 0 indicates the start of vitamin C administration. Data are from (A) Tan [103], (B) Kupari [90], and (C) Quinn [98]