What are the effects of vitamins E and C, beta-carotene, selenium and glutathione on lung disease in people with cystic fibrosis?

Background

Frequent chest infections in people with cystic fibrosis cause long-lasting inflammation in their lungs. Cells causing inflammation produce a kind of oxygen molecule (reactive oxygen species (ROS)) which can easily harm proteins and DNA (oxidative damage). To fight these effects, the body may produce antioxidants. The genetic defect in cystic fibrosis leads to an imbalance favouring the high production of harmful ROS over the low level of protective antioxidants. Antioxidant supplements might help reduce the oxidative damage in the lungs from constant infection and build up low levels of antioxidants.

There are many different antioxidants. Vitamin E and beta-carotene are fat-soluble and levels are low in people with cystic fibrosis because of the problems they have absorbing fat. Glutathione is the most abundant antioxidant in cells, but in people with cystic fibrosis it is not released into the lungs properly. Some enzymes which help antioxidants work are dependent on a mineral called selenium, so selenium supplements aim to stimulate antioxidant action. Vitamin C is water-soluble and decreases with age in people with cystic fibrosis, so vitamin C supplements aim to rebuild these levels.

Most supplements are taken by mouth, but glutathione can also be breathed directly into the lungs.

Search date

We last looked for evidence on 29th August 2013.

Study characteristics

We included 10 studies with 436 people with cystic fibrosis (almost equal numbers of males and females) aged from six months to 32.9 years. Eight studies compared oral supplements to placebo (a supplement appearing the same as the treatment but containing no medicine) and two compared inhaled supplements to placebo.

Key results

The main outcomes were lung function and quality of life; other outcomes were markers of oxidative stress, inflammation, body mass index, days on antibiotics and adverse events.

In one study (46 volunteers), a combined supplement showed a better score for forced expiratory volume at one second (% predicted) in the placebo group compared to the supplement group at two weeks, but a study of oral glutathione (41 children) showed that after six months people taking antioxidants had on average a 17.40% better score for this measure of lung function compared to the placebo group. The same study also showed a 14.80% better score for forced vital capacity for the supplemented group. The combined supplement study showed a improvement in quality of life in the placebo group. The oral glutathione study showed that those receiving glutathione had a body mass index on average 17.20% higher than the placebo group by the end of the study. All studies (regardless of the supplement) showed improvements in the blood levels of vitamin E. Those studies supplementing beta carotene and selenium also showed improvements in blood levels of those antioxidants.

The largest of the two inhaled glutathione studies (153 patients) showed that, compared to the placebo group, patients inhaling glutathione had on average a 2.57% better score for forced expiratory volume at one second (% predicted) after three months and a 0.96% better score after six months. We analysed quality of life data from this study, but found no difference between supplement and placebo groups.

Conclusions

It is too early to judge the effects of antioxidant supplements as the results of this review are conflicting and it is difficult to tell which changes are due to antioxidants and which are due to other treatments (e.g. antibiotics). Glutathione (either oral or inhaled) appears to improve lung function in some cases and lower oxidative stress. Larger studies, especially in very young patients, should look at important clinical outcomes for at least six months before firm conclusions regarding the effects of antioxidant supplements can be drawn.

Quality of the evidence

None of the studies was free of possible bias. Most problems were because data were not fully reported and we thought this likely to affect the results. We were mostly unsure if volunteers knew in advance which group they were going to be in and if they knew once the trials started whether they received the supplements or placebo. We are not sure how this might affect the results.

Authors' conclusions: 

There appears to be conflicting evidence regarding the clinical effectiveness of antioxidant supplementation in cystic fibrosis. Based on the available evidence, glutathione (administered either orally or by inhalation) appears to improve lung function in some cases and decrease oxidative stress; however, due to the very intensive antibiotic treatment and other treatments that cystic fibrosis patients receive, the beneficial effect of antioxidants is very difficult to assess in patients with chronic infection without a very large population sample and a long-term (at least six months) study period. Further studies, especially in very young patients, examining clinically relevant outcomes, dose levels, timing and the elucidation of clear biological pathways by which oxidative stress is involved in cystic fibrosis, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn.

Read the full abstract...
Background: 

Airway infection leads to progressive damage of the lungs in cystic fibrosis and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, ß-carotene and selenium) or glutathione may therefore potentially help maintain an oxidant-antioxidant balance. Current literature suggests a relationship between oxidative status and lung function.

Objectives: 

To synthesize existing knowledge of the effect of antioxidants such as vitamin C, vitamin E, ß-carotene, selenium and glutathione in cystic fibrosis lung disease.

Search strategy: 

The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies.

Last search of Cystic Fibrosis Trials Register: 29 August 2013.

Selection criteria: 

Randomized controlled studies and quasi-randomized controlled studies of people with cystic fibrosis comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care.

Data collection and analysis: 

Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted trial investigators to obtain missing information. Primary outcomes are lung function and quality of life; secondary outcomes are oxidative stress, inflammation, nutritional status, days on antibiotics and adverse events during supplementation. If meta-analysed, studies were subgrouped according to method of administration and the duration of supplementation.

Main results: 

One quasi-randomized and nine randomized controlled studies were included, with a total of 436 participants. Eight studies analyzed oral supplementation with antioxidants and two inhaled supplements.

One study (n = 46) of an oral combined supplement demonstrated a significant difference in forced expiratory volume at one second expressed as per cent predicted after two weeks in favour of the control group, mean difference -4.30 (95% confidence interval -5.64 to -2.96); however a further study (n = 41) of oral supplementation with glutathione showed a significant improvement in this outcome and in forced vital capacity after six months from the treatment start, mean difference 17.40 (95% confidence interval 13.69 to 21.11) and 14.80 (95% confidence interval 9.66 to 19.94) respectively. The combined supplement study also indicated a significant improvement in quality of life favouring control, mean difference -0.06 points on the quality of well-being scale (95% confidence interval -0.12 to -0.01). Based on one study (n = 41) of oral glutathione supplementation in children, the supplements had a positive effect on the nutritional status (body mass index %) of the patients, mean difference 17.20 (95% confidence interval 12.17 to 22.23). In two studies (n = 83) that supplemented vitamin E, there was an improvement after two months in the blood levels of vitamin E, mean difference 11.78 μM/L (95% confidence interval 10.14 to 13.42).

Based on one of the two studies of inhaled glutathione supplementation, there was an improvement in the forced expiratory volume at one second expressed as per cent predicted after three and six months (n = 153), mean difference 2.57 (95% confidence interval 2.24 to 2.90) and 0.97 (95% confidence interval 0.65 to 1.29) respectively. Only one of the studies reported quality of life data that could be analysed, but data showed no significant differences between treatment and control.

None of the 10 included studies was judged to be free of bias.

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