Suche
Tian T, Shao J, Shen Z, et al. Association between serum vitamin C and all-cause and cause-specific deaths: data from the National Health and Nutrition Examination Survey (NHANES 2003–2006).Nutrition. 2022;101:111696.
Study objective
To examine the nonlinear association between serum vitamin C and all-cause or cause-specific mortality
Key to take away
Vitamin C may not be as harmless as commonly believed.
design
National Health and Nutrition Examination Survey (NHANES 2003–2006) observational study
Participant
In this study, researchers analyzed data from participants in NHANES 2003-2006, specifically the two NHANES cycles (2003-2004 and 2005-2006) in which serum vitamin C concentrations were tested.
Of the original 20,470 participants, about half were excluded, primarily due to missing vitamin C data. Ultimately, 9,902 participants were included in the analysis.
The average age of the people included in the analysis was 45.6 years; 51.6% were female. Self-identified race/ethnicity was as follows: 72% non-Hispanic white, 11.2% black, 8% Mexican American, 3.5% other Hispanic, and 5.3% other race.
Interventions
Serum vitamin C level (mg/dL) was the primary exposure variable of interest.
Researchers discovered it using isocratic high-performance liquid chromatography in various laboratories.
Evaluated study parameters
Outcome variables included all-cause death and cause-specific death. The researchers obtained this data by matching the NHANES data with the National Death Index (NDI) records.
Primary outcome
This study was intended to examine the possibility that the dose response to vitamin C may not be linear (i.e., higher doses may not have the same benefits as low doses).
Key findings
During a median follow-up of 10.6 years, there were 1,558 deaths from all causes, including 320 from cancer, 374 from cardiovascular disease (CVD), and 120 from respiratory disease.
There was a significantly higher association between all-cause mortality and CVD-associated mortality for those in the lowest and highest quintiles of circulating vitamin C (U-shaped relationship curve).
The authors concluded: “Interestingly, serum vitamin C levels that were below the threshold (1.06 mg/dL) were negatively associated with all-cause (fully adjusted hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.590). 86) and CVD (fully adjusted HR: 0.70; 95% CI: 0.471.03) Mortality. In contrast, serum vitamin C levels above the threshold (1.06 mg/dL) were positive with all causes (fully adjusted HR, 1.33; 95% CI, 1.151.54) and CVD (fully adjusted HR, 1.60, 95) associated % CI, 1,232.10) mortality.
While the association between vitamin C, cancer and respiratory diseases did not reach statistical significance, there were clear trends in the data indicating a possible positive association for these diseases as well.
transparency
Funding source disclosed and no transparency concerns raised.
Implications and limitations for practice
If the results in this study by Tian et al. If the reported results are valid, we should question our long-held assumptions about the safety of water-soluble vitamins. Before examining the implications of these data, let us first consider the arguments for the validity of these results.
These results are based on epidemiological data rather than randomized clinical trials, and today there is a tendency to rely more on data from blind studies than on epidemiological data. Nevertheless, NHANES remains one of the most trustworthy cohorts for data collection and allowed the paper's authors to ignore many possible confounding factors.
When comparing study participant characteristics based on vitamin C concentrations, participants classified in quintile 5 (those with the highest vitamin C levels) were more likely to be white, better educated, more physically active, wealthier, and to consume more fruits and vegetables than those with lower vitamin C levels. They were also less likely to smoke, have diabetes, or be overweight (lowest mean body mass index (BMI) of all quintiles). Those in quintile 5 also had the lowest average homocysteine and C-reactive protein (CRP) levels of all participants. Based on these characteristics, it can be predicted that these people would have the lowest risk of death during the study period, but instead had a 77% higher risk of death than those in quintile 3, whose vitamin C levels were at or near the median study participants.
In recent years, it has become common practice in scientific publications to describe hormetic dose responses as U-shaped or J-shaped, with the term hormesis completely eliminated from discussion.
Second, although this association between high vitamin C levels and mortality or morbidity rates seems unexpected, this is not the first time such a nonlinear risk pattern has been reported. The authors note that this study was specifically designed to investigate this phenomenon, as reported in previous research.
In 2016, Cadeau et al. about vitamin C intake and breast cancer risk. They compared vitamin C intake in the 2,482 cases of invasive breast cancer that occurred in 57,403 postmenopausal women in a 581,085 person-year prospective cohort. They used food frequency questionnaires to estimate vitamin C intake and reported that while vitamin C supplement use was not associated with breast cancer risk in all quintiles, "vitamin C supplement use was associated with increased postmenopausal breast cancer risk."in women with high vitamin C intake from food. “Our data suggest a possible U- or J-shaped association between total vitamin C intake and postmenopausal breast cancer risk, which requires further investigation” (emphasis added).1
In 2018, a large review and meta-analysis by Jayedi et al., who examined "dietary antioxidants, circulating antioxidant concentrations, total antioxidant capacity, and risk of all-cause mortality," reported that while most antioxidants were associated with a lower risk of death, their composite data described a U-shaped association between vitamin C and mortality.2
Not all studies find this type of curve. The publication by Wang et al. in 2018 on a large Chinese cohort found that higher plasma vitamin C levels were associated with a lower risk of heart disease and cancer in randomly selected older subjects; This association followed a simpler, linear association.3
Those previous reports led to this current study, which aimed to find out whether gradually higher levels of vitamin C could influence risk. Previous studies have focused on comparing inadequate and sufficient concentrations, without assuming the possibility of a nonlinear relationship and suggesting that the relationship might shift at higher circulating concentrations.
In recent years, U-shaped dose responses have been reported for several other vitamins, which we have not previously been concerned about. In early 2022, Xu et al reported that high serum folate levels may increase the risk of cardiovascular disease in some populations.4A few months earlier, in September 2021, researchers reported that vitamin B12The association with all-cause mortality was also U-shaped and higher serum levels increased the risk of death.5
Although each of these relationships needs to be examined individually and in much greater depth before we can confirm or deny their validity, their collective publication in such a short period of time makes me wonder whether we are only seeing this new pattern now because researchers have only recently started looking for it, or whether they now simply feel comfortable reporting what they observe in their data.
The idea that different doses of a substance could have strikingly different effects on biological systems goes back to the Arndt-Schulz law, which describes such two-phase dose-response relationships. However, this concept was heavily “marginalized” for many years because it was closely linked to homeopathy. The use of the correct term hormesis to describe biphasic dose responses was a barrier to publication.6In recent years, it has become common practice in scientific publications to describe hormetic dose responses as U-shaped or J-shaped, with the term hormesis completely eliminated from discussion. This recent “acceptance” appears to have enabled the publication of a rapidly growing number of papers describing dose responses that clearly fit the definition of hormesis, even if simply described as U-shaped curves.
This recent paper by Tian et al. should certainly make us wonder whether many of our patients are doing themselves long-term harm by taking daily doses of vitamin C and maintaining more than adequate serum vitamin C levels. Previous efforts to study vitamin C first focused on the benefits of reducing the damage associated with deficiency and then examined the long-term benefits of vitamin C against a variety of diseases. This study could be one of the first to specifically look for long-term harms associated with consumption. Would we have even noticed a problem if we hadn't known to look for it?
Perhaps we should use the data from Tian et al. use and say that in the absence of concrete evidence of need, our goal should be to maintain serum vitamin C levels close to 1.06 mg/dL, or alternatively, the levels suggested by Jayedi et al. suggested daily dose of 125 mg/day to be used. I write “perhaps” because such suggestions may seem strikingly low-level to both patients and physicians and would require abandoning long-held assumptions.