Adding an orange to the banana bag: vitamin C deficiency is common in alcohol use disorders.

BACKGROUND: At least a third of the world's population consumes alcohol regularly. Patients with alcohol use disorders (AUDs) are frequently hospitalized for both alcohol-related and unrelated medical conditions. It is well recognized that patients with an AUD are thiamine deficient with thiamine replacement therapy being considered the standard of care. However, the incidence of vitamin C deficiency in this patient population has been poorly defined. METHODS: In this retrospective, observational study, we recorded the admission vitamin C level in patients with an AUD admitted to our medical intensive care unit (MICU) over a 1-year period. In addition, we recorded relevant clinical and laboratory data including the day 2 and day 3 vitamin C level following empiric treatment with vitamin C. Septic patients were excluded from this study. RESULTS: Sixty-nine patients met the inclusion criteria for this study. The patients' mean age was 53 ± 14 years; 52 patients (75%) were males. Severe alcohol withdrawal syndrome was the commonest admitting diagnosis (46%). Eighteen patients (26%) had cirrhosis as the admitting diagnosis with 18 (13%) patients admitted due to alcohol/drug intoxication. Forty-six patients (67%) had evidence of acute alcoholic hepatitis. The mean admission vitamin C level was 17.0 ± 18.1 µmol/l (normal 40-60 µmol/l). Sixty-one (88%) patients had a level less than 40 µmol/l (subnormal) while 52 patients (75%) had hypovitaminosis C (level < 23 µmol/l). None of the variables recorded predicted the vitamin C level. Various vitamin C replacement dosing strategies were used. A 1.5-g loading dose, followed by 500-mg PO q 6, was effective in restoring blood levels to normal by day 2. CONCLUSION: Our results suggest that hypovitaminosis C is exceedingly common in patients with an AUD admitted to an intensive care unit and that all such patients should receive supplementation with vitamin C in addition to thiamine. Additional studies are required to confirm the findings of our observational study and to determine the optimal vitamin C dosing strategy.

Lessons in early identification and treatment from a case of disabling vitamin C deficiency in a child with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder is a heterogenous neurodevelopmental condition accompanied by a variety of associated features. Case reports suggest one such associated feature, food selectivity, increases risk for nutritional deficiencies; however, little attention has been given to prevent and treat nutritional deficiencies in youth with autism spectrum disorder. METHOD: Single case report. RESULTS: This single case report presents a child with autism spectrum disorder and food selectivity difficulties that resulted in severe vitamin C deficiency. Although eventually corrected, the nutritional deficiency was debilitating, required invasive interventions, and resulted in significant social/emotional and economic costs. CONCLUSIONS: We review the course of treatment and highlight strategies to prevent and more effectively treat nutritional deficiencies in youth with autism spectrum disorder.

Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Vitamin D and/or calcium deficient diets may differentially affect muscle fiber neuromuscular junction innervation.

INTRODUCTION: There is evidence that supports a role for Vitamin D (Vit. D) in muscle. The exact mechanism by which Vit. D deficiency impairs muscle strength and function is not clear. METHODS: Three-week-old mice were fed diets with varied combinations of Vit. D and Ca2+ deficiency. Behavioral testing, genomic and protein analysis, and muscle histology were performed with a focus on neuromuscular junction (NMJ) -related genes. RESULTS: Vit. D and Ca2+ deficient mice performed more poorly on given behavioral tasks than animals with Vit. D deficiency alone. Genomic and protein analysis of the soleus and tibialis anterior muscles revealed changes in several Vit. D metabolic, NMJ-related, and protein chaperoning and refolding genes. CONCLUSIONS: These data suggest that detrimental effects of a Vit. D deficient or a Vit. D and Ca2+ deficient diet may be a result of differential alterations in the structure and function of the NMJ and a lack of a sustained stress response in muscles. Muscle Nerve 54: 1120-1132, 2016.

Role of vitamin C as an adjuvant therapy to different iron chelators in young ß-thalassemia major patients: efficacy and safety in relation to tissue iron overload.

BACKGROUND: Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). AIM: To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with ß-thalassemia major (ß-TM) in relation to tissue iron overload. METHODS: This randomized prospective trial that included 180 ß-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. RESULTS: Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. CONCLUSIONS: Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with ß-TM, with no adverse events.

Is Vitamin C Supplementation in Patients with ß-Thalassemia Major Beneficial or Detrimental?

Globally, ß-thalassemia major (ß-TM) is one of the most common hereditary disorders. Multiple blood transfusions, that are a life-saving therapy in patients with ß-TM, is a major source of iron overload. Iron overload can lead to significant morbidity and mortality. Research evidence indicates that oxidative stress induced by iron overload, is one of the major precipitating causes of vitamin C deficiency in ß-TM patients. It has previously been shown that patients with ß-TM have significantly lower levels of vitamin C as compared to healthy individuals. It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system. Despite the potential benefits of vitamin C in patients with ß-TM, several areas of concern exist that should be addressed by high quality research designs. Some recommendations have been provided through this study.

The lower vitamin C plasma concentrations in elderly men compared with elderly women can partly be attributed to a volumetric dilution effect due to differences in fat-free mass.

Women show higher vitamin C plasma concentrations than men, but the reasons for this observation still require elucidation. The objective of the present study was to investigate whether sex differences in vitamin C plasma concentrations are present in elderly subjects and whether these differences are due to sex-specific lifestyles, total antioxidant status (TAOS) and/or body composition. Fasting plasma concentrations of vitamin C were assessed by photometric detection in a cross-sectional study of 181 women and eighty-nine men aged 62-92 years. Body composition was determined by bioelectrical impedance analysis. Vitamin C intake was assessed with a 3 d estimated dietary record. Stepwise multiple regression analyses were performed to investigate whether sex is an independent predictor of vitamin C plasma concentrations by controlling for age, vitamin C intake, lifestyle factors, TAOS and body composition. Women showed higher vitamin C plasma concentrations than men (76 v. 62 µmol/l, P< 0·0001). In the multiple regression analysis, male sex was a negative predictor of vitamin C plasma concentrations (ß = -0·214), as long as absolute fat-free mass (FFM) was not considered as a confounder. When absolute FFM was included, sex was no longer a predictor of vitamin C plasma concentrations, whereas absolute FFM (ß = -0·216), physical activity level (ß = 0·165), intake of vitamin C supplements (ß = 0·164), age (ß = 0·147) and smoking (ß = -0·125) affected vitamin C plasma concentrations. The results indicate that a higher absolute FFM, and thus a higher distribution volume of vitamin C, contributes to lower vitamin C plasma concentrations in men than women.

Methemoglobinemia and ascorbate deficiency in hemoglobin E ß thalassemia: metabolic and clinical implications.

During investigations of the phenotypic diversity of hemoglobin (Hb) E ß thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE ß thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.

Vegetable and fruit consumption, education and plasma vitamin C concentration in Russian and Finnish Karelia, 1992-2002.

OBJECTIVE: To examine (i) whether the consumption of fresh vegetables, fruit and berries is associated with plasma vitamin C concentration and (ii) educational differences in plasma vitamin C concentration in two neighbouring areas in Russia and Finland. DESIGN: Cross-sectional risk factor surveys in 1992, 1997 and 2002. Logistic regression analysis was applied to examine the associations of consumption of selected foods and education with plasma vitamin C concentration. SETTING: District of Pitkäranta in the Republic of Karelia, Russia and North Karelia, Finland. SUBJECTS: Adults aged 25-64 years: 579 men and 612 women in Pitkäranta; 974 men and 642 women in North Karelia. RESULTS: The plasma vitamin C concentration was strikingly low in Pitkäranta, Russia across the study years. During the 10 years of monitoring, the mean plasma vitamin C concentration among men ranged from 2·5 to 8·0 µmol/l in Pitkäranta, Russia and from 27·1 to 53·9 µmol/l in North Karelia, Finland. In both areas, daily consumption of fruit was most strongly associated with plasma vitamin C, while the association of fresh vegetable consumption with plasma vitamin C was less consistent. Consumption of berries was less important in explaining plasma vitamin C. In Pitkäranta, the plasma vitamin C concentration was lower among respondents in the lowest education group. CONCLUSIONS: Differences in the consumption of fresh vegetables and fruit resulted in notable differences in vitamin C status between Pitkäranta and North Karelia in spring. In comparative settings, knowledge of local food culture and validation pilots are important before conducting large population surveys.

Is vitamin C intake too low in dialysis patients?

Vitamin C has several well-established roles in physiology including synthesis of collagen, carnitine and epinephrine, absorption of dietary iron, and mobilization of storage iron for erythropoeisis. Loss of several of these functions explains the pathology of scurvy, where defective collagen synthesis and anemia are major symptoms. Vitamin C deficiency is very common in dialysis patients and may arise from dialytic vitamin C clearance, restricted intake of vitamin C-rich foods, and increased vitamin C catabolism in vivo from inflammation. In the dialysis population, greater vitamin C intake may be needed for optimal health. Relationships between intake, body distribution, inflammation, and dialytic losses are complex and need further study. Concern about vitamin C metabolism leading to accumulation of tissue oxalate has led to the recommendation that vitamin C intake equals, but not exceeds, the intake recommended for the general population. Vitamin C deficiency in dialysis patients may have clinical consequences; a study in Renal Research Institute clinics found an association with periodontal disease. Data also support a role for vitamin C in prevention of dialysis-related anemia. New research questions are proposed in this editorial, with a discussion of strategies to determine the optimal provision of vitamin C for CKD patients.

Vitamin C in sepsis.

Bacterial bloodstream infection causes septic syndromes that range from systemic inflammatory response syndrome (SIRS) and encephalopathy to severe sepsis and septic shock. Microvascular dysfunction, comprising impaired capillary blood flow and arteriolar responsiveness, precedes multiple organ failure. Vitamin C (ascorbate) levels are low in critically ill patients. The impact of ascorbate administered orally is moderate because of its limited bioavailability. However, intravenous injection of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of polymicrobial sepsis, intravenous ascorbate injection restores microvascular function and increases survival. The protection of capillary blood flow and arteriolar responsiveness by ascorbate may be mediated by inhibition of oxidative stress, modulation of intracellular signaling pathways, and maintenance of homeostatic levels of nitric oxide. Ascorbate scavenges reactive oxygen species (ROS) and also inhibits the NADPH oxidase that synthesizes superoxide in microvascular endothelial cells. The resulting changes in redox-sensitive signaling pathways may diminish endothelial expression of inducible nitric oxide synthase (iNOS), tissue factor and adhesion molecules. Ascorbate also regulates nitric oxide concentration by releasing nitric oxide from adducts and by acting through tetrahydrobiopterin (BH4) to stimulate endothelial nitric oxide synthase (eNOS). Therefore, it may be possible to improve microvascular function in sepsis by using intravenous vitamin C as an adjunct therapy.

Scurvy in the Great Irish Famine: evidence of vitamin C deficiency from a mid-19th century skeletal population.

Scurvy has increasingly been recognized in archaeological populations since the 1980s but this study represents the first examination of the paleopathological findings of scurvy in a known famine population. The Great Famine (1845-1852) was a watershed in Irish history and resulted in the death of one million people and the mass emigration of just as many. It was initiated by a blight which completely wiped out the potato-virtually the only source of food for the poor of Ireland. This led to mass starvation and a widespread occurrence of infectious and metabolic diseases. A recent discovery of 970 human skeletons from mass burials dating to the height of the famine in Kilkenny City (1847-1851) provided an opportunity to study the skeletal manifestations of scurvy-a disease that became widespread at this time due to the sudden lack of Vitamin C which had previously almost exclusively been provided by the potato. A three-scale diagnostic reliance approach has been employed as a statistical aid for diagnosing the disease in the population. A biocultural approach was adopted to enable the findings to be contextualized and the etiology and impact of the disease explored. The results indicate that scurvy indirectly influenced famine-induced mortality. A sex and stature bias is evident among adults in which males and taller individuals displayed statistically significantly higher levels of scorbutic lesions. The findings have also suggested that new bone formation at the foramen rotundum is a diagnostic criterion for the paleopathological identification of scurvy, particularly among juveniles.

Plasma vitamin C concentrations in patients on routine hemodialysis and its relationship to patients' morbidity and mortality.

BACKGROUND: Some studies have hypothesized the protective role of vitamin C against cardiovascular disorders (CVD) in patients with end-stage renal disease (ESRD). This study was designed to assess plasma vitamin C concentration and its relationship to hemodialysis (HD) patients' morbidity and mortality. METHODS: Plasma vitamin C concentrations were assessed in HD patients using spectrophotometry and subjects were prospectively followed for up eighteen months for all-cause mortality. Any association between vitamin C concentration and patients' demographic data, co-morbidities, or the cause of ESRD were investigated using the Chi-square test. RESULTS: Ninety-one patients with a mean age of 56.7 ± 15.7 years were included in this study. The most frequent cause of ESRD was simultaneous hypertension and diabetes in 30 % of patients, followed by hypertension in 25.6 %, and diabetes in 11.1 %, respectively. About 34 % of patients had CVD as the most prevalent co-morbidity. Forty-nine patients (53.8 %) had low levels of vitamin C concentration. There was a significant relationship between vitamin C insufficiency and presence of any co-morbidity in HD patients (p < 0.05). There was a significant difference in vitamin C concentrations between patients without co-morbidities and those with cardiovascular ones (F[2,88]=3.447, p = 0.036). Twenty-two (24.2 %) patients died over a median duration of 227 days. There was a significant difference in time to death of patients with and without low levels of vitamin C concentration (p = 0.04). CONCLUSIONS: The results showed lower plasma vitamin C levels in HD patients who suffered any co-morbidity and sooner time to death in these patients.

[Anti-aging research using SMP30/GNL knockout mice].

Senescence Marker Protein-30 (SMP30) was originally identified as a novel protein in the rat liver, the expression of which decreases with aging. Recently, we identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonases (GNL) of animal species. GNL was a key enzyme which involved in vitamin C biosynthesis, and the essential role of SMP30 in this synthetic process was verified by a nutritional study. SMP30 knockout mice developed symptoms of scurvy when fed a vitamin C-deficient diet, verifying the pivotal role of SMP30 in vitamin C biosynthesis. Moreover, SMP30 knockout mice were shorter in life span than the wild type when fed autoclaved mouse chow contained approximately 55 mg/kg of vitamin C, which we now know contains too little vitamin C to maintain normal levels of vitamin C in tissues. These results demonstrate that vitamin C deficiency shortens longevity, that is, vitamin C deficiency accelerates aging.

Patients Undergoing Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation Exhibit Depleted Vitamin C Status in Association with Febrile Neutropenia.

Patients undergoing myeloablative chemotherapy and hematopoietic stem cell transplantation (HSCT) experience profound neutropenia and vulnerability to infection. Previous research has indicated that patients with infections have depleted vitamin C status. In this study, we recruited 38 patients with hematopoietic cancer who were undergoing conditioning chemotherapy and HSCT. Blood samples were collected prior to transplantation, at one week, two weeks and four weeks following transplantation. Vitamin C status and biomarkers of inflammation (C-reactive protein) and oxidative stress (protein carbonyls and thiobarbituric acid reactive substances) were assessed in association with febrile neutropenia. The vitamin C status of the study participants decreased from 44 ± 7 µmol/L to 29 ± 5 µmol/L by week one (p = 0.001) and 19 ± 6 µmol/L by week two (p < 0.001), by which time all of the participants had undergone a febrile episode. By week four, vitamin C status had increased to 37 ± 10 µmol/L (p = 0.1). Pre-transplantation, the cohort comprised 19% with hypovitaminosis C (i.e., <23 µmol/L) and 8% with deficiency (i.e., <11 µmol/L). At week one, those with hypovitaminosis C had increased to 38%, and at week two, 72% had hypovitaminosis C, and 34% had outright deficiency. C-reactive protein concentrations increased from 3.5 ± 1.8 mg/L to 20 ± 11 mg/L at week one (p = 0.002), and 119 ± 25 mg/L at week two (p < 0.001), corresponding to the development of febrile neutropenia in the patients. By week four, these values had dropped to 17 ± 8 mg/L (p < 0.001). There was a significant inverse correlation between C-reactive protein concentrations and vitamin C status (r = -0.424, p < 0.001). Lipid oxidation (thiobarbituric acid reactive substances (TBARS)) increased significantly from 2.0 ± 0.3 µmol/L at baseline to 3.3 ± 0.6 µmol/L by week one (p < 0.001), and remained elevated at week two (p = 0.003), returning to baseline concentrations by week four (p = 0.3). Overall, the lowest mean vitamin C values (recorded at week two) corresponded with the highest mean C-reactive protein values and lowest mean neutrophil counts. Thus, depleted vitamin C status in the HSCT patients coincides with febrile neutropenia and elevated inflammation and oxidative stress.

Vitamin C in Home Parenteral Nutrition: A Need for Monitoring.

To date, there are no recommendations about screening plasma vitamin C concentration and adjust its supplementation in patients on long-term home parenteral nutrition (HPN). The aim of this study was to evaluate vitamin C status and determine if a commercial multivitamin preparation (CMVP) containing 125 mg of vitamin C is sufficient in stable patients on HPN. All clinically stable patients receiving HPN or an intravenous fluid infusion at least two times per week for at least 6 months, hospitalized for nutritional assessment, were retrospectively included, for a total of 186 patients. We found that 29% of the patients had vitamin C insufficiency (i.e., <25 µmol/L). In univariate analysis, C-reactive protein (CRP) (p = 0.002) and intake of only 125 mg of vitamin C (p = 0.001) were negatively associated with vitamin C levels, and duration of follow-up in our referral center (p = 0.009) was positively associated with vitamin C levels. In multivariate analysis, only CRP (p = 0.001) and intake of 125 mg of vitamin C (p < 0.0001) were independently associated with low plasma vitamin C concentration. Patients receiving only CMVP with a low plasma vitamin C level significantly received personal compounded HPN (p = 0.008) and presented an inflammatory syndrome (p = 0.002). Vitamin C insufficiency is frequent in individuals undergoing home parenteral nutrition; therefore, there is a need to monitor plasma vitamin C levels, especially in patients on HPN with an inflammatory syndrome and only on CMVP.

Vitamin C Deficiency and the Risk of Osteoporosis in Patients with an Inflammatory Bowel Disease.

Recent research studies have shown that vitamin C (ascorbic acid) may affect bone mineral density and that a deficiency of ascorbic acid leads to the development of osteoporosis. Patients suffering from an inflammatory bowel disease are at a risk of low bone mineral density. It is vital to notice that patients with Crohn's disease and ulcerative colitis also are at risk of vitamin C deficiency which is due to factors such as reduced consumption of fresh vegetables and fruits, i.e., the main sources of ascorbic acid. Additionally, some patients follow diets which may provide an insufficient amount of vitamin C. Moreover, serum vitamin C level also is dependent on genetic factors, such as SLC23A1 and SLC23A2 genes, encoding sodium-dependent vitamin C transporters and GSTM1, GSTP1 and GSTT1 genes which encode glutathione S-transferases. Furthermore, ascorbic acid may modify the composition of gut microbiota which plays a role in the pathogenesis of an inflammatory bowel disease.

Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the Intensive Care Unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and hematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, an established marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs. 56 ± 24 µmol/L, p < 0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs. 24 ± 14 µmol/L, p = 0.02). The pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (p < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples from 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (p = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease excessive oxidative stress and aid in their recovery.