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

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.

Vitamin C Deficiency as a Mimicker of a Coagulation Disorder.

Scurvy is caused by vitamin C deficiency and is often thought of as an ancient malady. However, it still afflicts present-day patients with insufficient nutrition, excessive alcohol consumption and disorders of absorption. Scurvy is traditionally characterised by ecchymosis, petechiae, haemorrhages, poor wound healing, myalgias and arthralgias, but it can also present with non-specific symptoms, including mood changes, fatigue, malaise and dyspnoea. Although scurvy can present with signs of excess bleeding, it does not involve blood clotting. We present a case of concurrent scurvy and pulmonary embolism in which clinical presentation and laboratory findings mimicked a coagulation disorder, resulting in delayed diagnosis and excessive resource expenditure. This case underscores the importance of obtaining an early dietary and substance use history in patients with unexplained haematological symptoms. These crucial components of history-taking can significantly reduce invasive and costly tests, resulting in quicker diagnosis and enhanced patient outcomes.

Ascorbic acid deficiency amongst spondylodiscitis patients.

BACKGROUND: Spondylodiscitis can be a disabling and life-threatening infection. Ascorbic Acid is crucial for neutrophil function and collagen formation. Its association and clinical relevance in spondylodiscitis has not been previously examined. AIMS: To determine the prevalence, characteristics, and clinical outcomes of spondylodiscitis patients with Ascorbic Acid deficiency. METHODS: Sixty-eight consecutive patients admitted with spondylodiscitis, between December 2021 and August 2023 were included. Clinical characteristics, Ascorbic Acid levels and clinical outcomes were evaluated. RESULTS: Thirty-seven patients had Ascorbic Acid levels taken during admission. The median initial Ascorbic Acid level was 15 µmol/L with an IQR 6.5-27 µmol/L. Depletion defined as <28 µmol/L was present in 78% of patients. Deficiency defined as ≤11 µmol/L was present in and 46% of patients. Patients with depletion were more likely to require Intensive Care Admission (absolute risk increase = 24.1%; 2.6%-45.7%). Fifteen patients had repeat serum levels taken during admission with median increase of 17 µmol/L and an IQR 0-26 µmol/L. Patients that received supplementation had a significantly greater increase in Ascorbic Acid levels compared with those that did not receive supplementation (P = 0.002). CONCLUSION: Ascorbic acid deficiency is highly prevalent amongst spondylodiscitis patients. Depletion was associated with worse outcomes. Replacement significantly increased serum levels in comparison to standard hospital diet. The clinical significance of replacement remains to be evaluated.

Interleukin-8 and neutrophil extracellular traps in children with lupus nephritis and vitamin C deficiency.

BACKGROUND: Vitamin C is a potent scavenger of reactive oxygen species, which induce neutrophil extracellular trap (NET) formation. NETs are a major source of autoantigens and are involved in systemic lupus erythematosus (SLE) pathogenesis. We determined vitamin C status and evaluated NET formation and inflammatory cytokines in children with lupus nephritis. METHODS: Serum vitamin C was measured in 46 patients (82.6% females, mean age 14.5 ± 0.3 years). Vitamin C levels < 0.3 mg/dL indicated vitamin C deficiency. Patients were divided into two groups according to serum vitamin C levels: normal and low (< 0.3 mg/dL). We compared NET formation and levels of SLE-related cytokines, including interleukin (IL)-8, IL-10, and tumor necrosis factor-α (TNF-α), between groups. NET formation was determined through measurement of serum citrullinated histone 3 levels and mRNA expression of peptidyl arginine deiminase-4 and assessment of the percentage of neutrophils with NETs by immunofluorescence. RESULTS: Nine patients (19.6%) had vitamin C deficiency. Kidney pathology assessment at disease onset revealed that histological activity index and number of kidney biopsies containing crescentic glomeruli were higher in vitamin C-deficient patients, but chronicity index was not. NET formation and serum IL-8 were more prominent in vitamin C-deficient patients. Serum IL-8 levels were 12.9 ± 5.2 pg/mL in low vitamin C group and 5.2 ± 0.9 pg/mL in normal vitamin C group (p = 0.03). Serum IL-10 and TNF-α were similar between groups. CONCLUSIONS: Our study demonstrated correlation among vitamin C deficiency, increased NET formation, and IL-8 upregulation in children with lupus nephritis. A prospective study is required to evaluate cause‒effect relationships of vitamin C status, NET formation and IL-8 expression.

Severe vitamin C deficiency associated with continuous renal replacement therapy: A case report.

Hypovitaminosis C is prevalent in critically ill patients. Continuous renal replacement therapy (CRRT) clears vitamin C, increasing the risk for vitamin C deficiency. However, recommendations for vitamin C supplementation in critically ill patients receiving CRRT vary widely, from 250 mg/day to 12 g/day. This case report describes a patient who developed a severe vitamin C deficiency after prolonged CRRT despite receiving ascorbic acid (450 mg/day) supplementation in her parenteral nutrition. This report summarizes recent research investigating vitamin C status in critically ill patients receiving CRRT, discusses the patient case, and provides recommendations for clinical practice. In critically ill patients receiving CRRT, the authors of this manuscript suggest providing at least 1000 mg/day of ascorbic acid to prevent vitamin C deficiency. Baseline vitamin C levels should be checked in patients who are malnourished and/or have other risk factors for vitamin C deficiency, and vitamin C levels should be monitored thereafter every 1-2 weeks.

Pseudoparalysis Secondary to Vitamin C Deficiency: A Rare Presentation in a Toddler.

CASE: We present a 17-month-old girl with postencephalitic sequelae only on high-calorie cereal milk through a nasogastric tube. She presented with a 3-week history of swelling and decreased lower limb movements. Synovial fluid analysis ruled out septic arthritis. Plain radiograph and magnetic resonance imaging (MRI) were suggestive of scurvy. She was diagnosed to have pseudoparalysis secondary to scurvy. She was started on vitamin C supplements, after which she showed good clinical improvement. CONCLUSION: This case report is to re-emphasize the need for awareness of the possibility of scurvy in children with poor nutritional status due to feeding difficulties.

Risk of Hypovitaminosis and Vitamin C Deficiency in Pediatric Patients Undergoing Cardiopulmonary Bypass.

Vitamin C levels are known rapidly decrease in adult critical illness. Vitamin C scavenges free radicals, provides critical protection of the endothelial barrier, and improves endothelial responsiveness to catecholamines. Children with congenital heart disease and undergoing cardiac surgery might be at increased risk for low circulating vitamin C levels. A prospective single-center observational study investigated perioperative changes in vitamin C levels in critically ill Children who underwent congenital heart surgery using CPB. Vitamin C serum levels were collected preoperatively and postoperatively (upon admission to the ICU, 24 and 72 h). Linear mixed-effect model was used to estimate mean circulating concentration of vitamin C and to estimate changes in concentration over time. Primary outcome was change in circulating levels of vitamin C before and after CPB. Secondary outcomes were hospital length of stay (LOS), acute kidney injury (AKI), and illness severity. Forty-one patients with a median age of 4.5 [interquartile range (IQR) 2.6-65.6] months at the time of surgery were consented and enrolled. Median CPB duration was 130 [90-175] minutes, and hospital LOS was 9.1 [5.2-19] days. Mean vitamin C levels (µmol/L) before CPB, at PICU admission, 24 h, and 72 h were 82.0 (95% CI 73.4-90.7), 53.4 (95% CI 44.6,62.0), 55.1 (95% CI 46.3,63.8), and 59.2 (95% CI 50.3,68.1), respectively. Upon postoperative admission to the PICU, vitamin C levels decreased by 28.7 (95% CI 20.6-36.8; p < 0.001) µmol/L, whereas levels at 24 and 72 h recovered and did not differ substantially from concentrations reported upon PICU admission (p > 0.15). Changes in vitamin C concentration were not associated with CPB time, STAT mortality category, age, or PIM3. Three patients had post-CPB hypovitaminosis C or vitamin C deficiency. Reduction in vitamin C levels was not associated with hospital LOS (p = 0.673). A 25 µmol/L decrease in vitamin C levels upon PICU admission was associated with developing AKI (aOR = 3.65; 95% CI 1.01-18.0, p = 0.049). Pediatric patients undergoing cardiac surgery with CPB showed decreased vitamin C levels during the immediate postoperative period. Effects of hypovitaminosis C and vitamin C deficiency in this population remain unclear.

Vitamin C Urinary Loss and Deficiency in Human Immunodeficiency Virus (HIV): Cross-sectional Study of Vitamin C Renal Leak in Women With HIV.

BACKGROUND: Reduced plasma vitamin C (vitC) concentrations in human immunodeficiency virus (HIV) may result from abnormal urinary excretion: a renal leak. VitC renal leak indicates underlying nutritional dysregulation independent of diet. We hypothesized that increased renal leak prevalence in HIV would be associated with deficient vitC concentrations. METHODS: We conducted an outpatient cross-sectional study of 96 women (40 HIV [PWH] and 56 without HIV [PWOH]) at the National Institutes of Health and Georgetown University. Renal leak was defined as abnormal urinary vitC excretion at fasting plasma concentrations <43.2µM, 2 SDs below vitC renal threshold in healthy women. To determine the primary outcome of renal leak prevalence, matched urine and plasma samples were collected the morning after overnight fast. Secondary outcomes assessed group differences in mean plasma vitC concentrations and prevalence of vitC deficiency. Exploratory outcomes assessed clinical parameters associated with renal leak. VitC was measured by high-performance liquid chromatography with coulometric electrochemical detection. RESULTS: PWH had significantly higher renal leak prevalence (73%vs14%; OR (odds ratio):16; P<.001), lower mean plasma vitC concentrations (14µMvs50µM; P<.001), and higher prevalence of vitC deficiency (43%vs7%; OR:10; P<.001) compared with PWOH, unchanged by adjustments for confounding factors. Significant predictors of renal leak included antiretroviral therapy (ART), Black race, older age, and metabolic comorbidities but not viral load or CD4 count. When compared with other chronic disease cohorts, PWH had the highest prevalence of renal leak and vitC deficiency (P<.001). CONCLUSIONS: High prevalence of vitC renal leak in HIV was associated with vitC deficiency, ART use, and race/ethnicity differences.

Difficult to think about but easy to treat: scurvy.

OBJECTIVES: Severe vitamin C deficiency, or scurvy, presents as a syndrome of multisystem abnormalities associated with defective collagen synthesis and antioxidative functions. The many clinical features of scurvy lead to frequent misdiagnoses, as they can often point to other diseases, such as vasculitis, venous thrombosis and musculoskeletal disorders. As such, an extensive workup is recommended in cases in which scurvy is suspected. CASE PRESENTATION: A 21-month-old male patient and a 36-month-old female patient presented with difficulty in walking, painful joint movements, irritability, gingival hypertrophy and bleeding. After exhaustive investigations and risky invasive procedures, vitamin C deficiency was diagnosed in both cases, and the symptoms improved dramatically with vitamin C treatment. CONCLUSIONS: The importance of taking a dietary history in pediatric patients is highly recommended. In cases where scurvy is considered, serum ascorbic acid levels should be checked to confirm the diagnosis prior to conducting invasive tests.

Scurvy-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that results in precapillary pulmonary hypertension. PAH is caused by a group of clinical conditions involving multiple organ systems. Several cases have been reported in the literature demonstrating an association between vitamin C deficiency and PAH. Low endothelial nitric oxide levels in the pulmonary vasculature, combined with the inappropriate activation of hypoxia-inducible transcription factors, seen in patients with ascorbic acid deficiency, are believed to be the main contributors to the pathogenesis of pulmonary vasculopathy and the exaggerated pulmonary vasoconstrictive response seen in patients with scurvy-induced PAH. Vitamin C supplementation is considered the definitive treatment.

What We Are Missing: Using Machine Learning Models to Predict Vitamin C Deficiency in Patients with Metabolic and Bariatric Surgery.

PURPOSE: Vitamin C (VC) is implicated in many physiological pathways. Vitamin C deficiency (VCD) can compromise the health of patients with metabolic and bariatric surgery (patients). As symptoms of VCD are elusive and data on VCD in patients is scarce, we aim to characterize patients with measured VC levels, investigate the association of VCD with other lab abnormalities, and create predictive models of VCD using machine learning (ML). METHODS: A retrospective chart review of patients seen from 2017 to 2021 at a tertiary care center in Northeastern USA was conducted. A 1:4 case mix of patients with VC measured to a random sample of patients without VC measured was created for comparative purposes. ML models (BayesNet and random forest) were used to create predictive models and estimate the prevalence of VCD patients. RESULTS: Of 5946 patients reviewed, 187 (3.1%) had VC measures, and 73 (39%) of these patients had VC<23 µmol/L(VCD. When comparing patients with VCD to patients without VCD, the ML algorithms identified a higher risk of VCD in patients deficient in vitamin B1, D, calcium, potassium, iron, and blood indices. ML models reached 70% accuracy. Applied to the testing sample, a "true" VCD prevalence of ~20% was predicted, among whom ~33% had scurvy levels (VC<11 µmol/L). CONCLUSION: Our models suggest a much higher level of patients have VCD than is reflected in the literature. This indicates a high proportion of patients remain potentially undiagnosed for VCD and are thus at risk for postoperative morbidity and mortality.

[Scurvy still occurs]. / Scheurbuik komt nog steeds voor.

Scurvy is taught in history class and most doctors consider it a disease of the past. However, several studies show that vitamin C deficiency is highly prevalent among alcoholics, but also in elderly, people with low socioeconomic status, mental disorders or a restricted diet (7.1 - 25%). Besides the classical signs of scurvy, individuals exhibit a wide variety of symptoms. We present three recent cases of patients with vitamin C deficiency, with symptoms of bleeding, lethargy and edema, in whom supplementation greatly improved symptoms. As our cases illustrate having a high suspicion of scurvy and starting ascorbic acid might be a low cost and very effective intervention.

Rheumatologic manifestations with elevated levels of IL-6, IL-17A, and IL-23 in a patient with scurvy.

Symptomatic vitamin C deficiency, scurvy, is a relatively rare disease in developed countries, but it has been reported in patients with autism spectrum disorder or developmental delay who tend to have selective diets. Patients with scurvy often demonstrate musculoskeletal manifestations with unknown pathophysiology. Herein, we report a case of scurvy in an 11-year-old boy who presented with iron-deficiency anaemia, systemic osteomyelitis, myositis predominantly in the lower extremities, and right ventricular volume overload with mild pulmonary hypertension and was diagnosed with scurvy. He had a mild developmental disorder and a selective diet, which resulted in severe vitamin C deficiency. He received intravenous and oral vitamin C supplementation, which relieved his arthralgia and muscle pain in a week. Following 4 months of vitamin C supplementation, he demonstrated no abnormal manifestations on laboratory or imaging examination and recovered without sequelae. Inflammatory cytokine and chemokine evaluations demonstrated elevated levels of interleukin (IL)-6, IL-17A, and IL-23, which are associated with T-helper (Th) 17 cell activation. This study is the first to suggest the association between the inflammation seen in scurvy, rheumatic manifestations in the patient, and Th17 cell activation. Further analysis of the association between the inflammation and vitamin C supplementation may contribute to new insights for the comprehension and treatment of other inflammatory diseases, such as rheumatic diseases.

Clinical and molecular characteristics associated with Vitamin C deficiency in myeloid malignancies; real world data from a prospective cohort.

Vitamin C is an essential vitamin that acts as a co-factor for many enzymes involved in epigenetic regulation in humans. Low vitamin C levels in hematopoietic stem cells (HSC) promote self-renewal and vitamin C supplementation retards leukaemogenesis in vitamin C-deficient mouse models. Studies on vitamin C levels in patients with myeloid malignancies are limited. We thus conducted a retrospective analysis on a prospective cohort of patients with myeloid malignancies on whom plasma vitamin C levels were measured serially at diagnosis and during treatment. Baseline characteristics including hematological indices, cytogenetics, and molecular mutations are described in this cohort. Among 64 patients included in our study, 11 patients (17%) had low vitamin C levels. We noted a younger age at diagnosis for patients with myeloid malignancies who had low plasma vitamin C levels. Patients with low plasma vitamin C levels were more likely to have acute myeloid leukemia compared to other myeloid malignancies. Low vitamin C levels were associated with ASXL1 mutations. Our study calls for further multi-institutional studies to understand the relevance of low plasma vitamin C level in myeloid neoplasms, the role of vitamin C deficiency in leukemogenesis, and the potential benefit of vitamin C supplementation.

Prevalence and prognostic significance of vitamin C deficiency in patients with acute upper gastrointestinal bleeding: a prospective cohort study.

BACKGROUND: Vitamin C is an essential dietary nutrient important for collagen synthesis, including within the gastrointestinal tract. AIM: We aimed to document the prevalence of Vitamin C deficiency (VCD) in patients who present with upper gastrointestinal bleeding (UGIB) and its association with clinical outcomes. METHODS: We conducted a prospective cohort study of patients presenting with UGIB. Fasting Vitamin C levels were collected at admission. Primary outcomes were the prevalence of VCD (Vitamin C level <23 µmol/L, severe VCD < 12 µmol/L) and a composite outcome of adverse events, stratified by VCD status. Secondary outcomes were prolonged hospitalisation and the need for ICU admission. RESULTS: A total of 227 patients were included (mean age 64.5 years, males 63.9%). VCD was identified in 74 (32.6%) and severe deficiency in 32 (14.1%) patients. VCD was associated with a higher composite endpoint of AE (45.9% vs 24.8%, p < 0.01), higher in-hospital mortality (9.5% vs 1.3%, p < 0.01), increased prolonged admissions (62.2% versus 47.1%, p = 0.03) and increased rebleeding (17.6% vs 7.8%, p = 0.03), compared with patients with normal Vitamin C levels. Multivariate logistic regression models showed that VCD was independently associated with the composite endpoint of AE. CONCLUSION: VCD is highly prevalent in patients with UGIB and associated with poorer outcomes, including higher mortality, rebleeding and length of stay. Interventional studies are required to determine the impact of early Vitamin C supplementation on clinical outcomes.

Gait Disturbance of Red Herrings, Oranges, and Lemons - A Case of Missed Vitamin C Deficiency and Lessons Learnt.

Vitamin C deficiency resulting in scurvy, is considered to be a rare nutritional disorder in developed countries, thus leading to underdiagnosis with exposure to unnecessary investigations and delay in appropriate treatment. The wide myriad of clinical signs and symptoms with which vitamin C deficiency can present (including haematological, musculoskeletal and vague constitutional symptoms that overlap with other common medical conditions), also contributes to this diagnostic challenge. Despite scurvy being habitually thought to be present in children with neurodevelopmental conditions such as autism spectrum disorder, other important at-risk groups that frequently tend to be forgotten include children with persistent fussy eating behaviour, and children with abnormal vitamin C metabolism. We hereunder present a case of a 10-year-old boy who presented to an acute general hospital for further investigation with gait disturbance. The lack of detailed nutritional assessment on presentation in the first instance led to a missed diagnosis of vitamin C deficiency, thus exposing the child to a wide array of unnecessary investigations and treatments. The added perplexity to the case resulting from false positive results of investigations performed as part of this child's workup, is also discussed.

Prevalence and factors associated with vitamin C deficiency in inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are prone to several nutritional deficiencies. However, data are lacking on vitamin C deficiency in Crohn's disease (CD) and ulcerative colitis (UC) patients, as well as the impact of clinical, biomarker and endoscopic disease severity on the development of vitamin C deficiency. AIM: To determine proportions and factors associated with vitamin C deficiency in CD and UC patients. METHODS: In this retrospective study, we obtained clinical, laboratory and endoscopic data from CD and UC patients presenting to the IBD clinic at a single tertiary care center from 2014 to 2019. All patients had an available plasma vitamin C level. Of 353 subjects who met initial search criteria using a cohort discovery tool, 301 ultimately met criteria for inclusion in the study. The primary aim described vitamin C deficiency (≤ 11.4 µmol/L) rates in IBD. Secondary analyses compared proportions with deficiency between active and inactive IBD. Multivariate logistic regression analysis evaluated factors associated with deficiency. RESULTS: Of 301 IBD patients, 21.6% had deficiency, including 24.4% of CD patients and 16.0% of UC patients. Patients with elevated C-reactive protein (CRP) (39.1% vs 16.9%, P < 0.001) and fecal calprotectin (50.0% vs 20.0%, P = 0.009) had significantly higher proportions of deficiency compared to those without. Penetrating disease (P = 0.03), obesity (P = 0.02) and current biologic use (P = 0.006) were also associated with deficiency on univariate analysis. On multivariate analysis, the objective inflammatory marker utilized for analysis (elevated CRP) was the only factor associated with deficiency (odds ratio = 3.1, 95% confidence interval: 1.5-6.6, P = 0.003). There was no difference in the presence of clinical symptoms of scurvy in those with vitamin C deficiency and those without. CONCLUSION: Vitamin C deficiency was common in IBD. Patients with elevated inflammatory markers and penetrating disease had higher rates of vitamin C deficiency.