Beta Carotene Use in Cystic Fibrosis
ARBOR CLINICAL NUTRITION UPDATES ©
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This week we consider some new findings regarding nutritional aspects of cystic fibrosis (CF).

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NUTRITION RESEARCH REVIEW


Study 1: Carotene supplements help
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ß-carotene supplementation decreases lipid peroxidation and the need for antibiotic treatment, according to recently published Austrian research.

Subjects: 24 patients with CF (average age 13 years) and 14 age matched controls.

Method: Randomised, double-blind placebo-controlled clinical intervention in CF patients. Observation for 3 months prior to treatment, then active intervention consisted of ß-carotene in high dose (1mg/kg to a maximum of 50mg/day) for 3 months followed by low dose (10mg.day) for a further 3 months.

Results: The CF patients had significantly lower baseline ß-carotene levels than the healthy controls. Supplementation significantly elevated the CF patient's ß-carotene levels and reduced the number of days of antibiotic treatment they required, with some evidence of a dose-response effect - see Table.

By comparison, the placebo-treated CF patients experienced a rise in the number of antibiotic treatment days over the study period.

Supplementation also produced a fall in lipid peroxidation (plasma malondialdehyde), but no significant change in other clinical parameters assessed.


Table: Parameters in the ß-carotene supplemented group

Pre- ß-carotene  interv.  

                                    50mg     10mg     Signif.
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Plasma ß-carotene     0.08     0.56         0.32 p< 0.001
(µmol/L)

Antibiotic days             14.5     9.8           10.5 p<0.04            

                            (SD)  (14.9)  (10.3)     (9.9)



Reference: Thorax 2001 Jan;56(1):48-52 and Ann Nutr Metab 2000;44(1):30-7

Study 2: Acute treated episodes bring oxidative stress
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Acute treated episodes of respiratory infection in patients with cystic fibrosis are associated with a sharp increase in oxidative stress, along with increased fatty acid concentrations, according to recent Australian research.

Subjects: 15 CF patients undergoing intravenous antibiotic therapy for acute pulmonary exacerbation.

Method: Observational study in which measurement was taken before and after treatment. Dietary history was taken, along with assays for status of oxidative stress (8-iso-prostaglandin F2 alpha), plasma fatty acids and various antioxidants (including vitamins A/C/E selenium, erythrocyte glutathione, glutathione peroxidase and superoxide dismutase activity).

Results: Despite no change in dietary intake of antioxidants and an improvement in clinical status, there was a fall in erythrocyte glutathione peroxidase activity (but not of superoxide dismutase activity, nor of plasma vitamins C, E or ß-carotene).

There was a 20% rise in oxidative stress (from 469 to 565 mmolL 8-iso-PGF2 alpha, p =0.008). This was strongly correlated with a rise in plasma fatty acid concentration (r = 0.768, p =0.001).

Reference: Am J Clin Nutr 2002 Apr;75(4):668-75


COMMENTARY

Trying to normalise nutritional status in patients with CF is an ongoing struggle against the collective forces of malabsorption, decreased appetite due to recurrent sickness, increased nutrient requirements from growth (in children and adolescents), respiratory effort and recurrent infections, etc.

These factors have a strong tendency to interact in a negative way. For example, malnutrition makes the patient more susceptible to infection, impaired respiratory function, and all this leads to poorer long term outcome and higher mortality (ref.1).

Much effort has been directed to finding the best ways to improve nutrient status and increase lean body weight in CF patients, but this can be hard to achieve. Many different approaches have been tried, with the focus being on producing weight gain.

Although there is debate about the role of the more intensive and expensive approaches to providing nutrition support (including parenteral nutrition) (ref.2), there is no question that a long term, highly proactive approach is required if significant progress is to be maintained (ref.3).

It is therefore not surprising that the reported prevalence of malnutrition amongst CF patients, whilst varying widely, is usually high (typically of the order of 20% or higher - ref. 4).

Protein-energy malnutrition is the most common nutritional deficiency reported in CF patients (ref.3) . However, another important issue is fat malabsorption the associated deficiency of fat-soluble nutrients (including antioxidants such as vitamins A, E) and the interaction between these two
problems.

Fat and antioxidants
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CF patients tend to have disturbed essential fatty acid (EFA) profiles or outright EFA deficiency (ref. 5). Appropriate supplementation can at least partially correct these imbalances with benefit to the patient's weight and growth (ref. 6).

However, if antioxidant deficiencies are not also corrected, measures which increase fatty acid levels may also increase the risk of tissue damage through the oxidative stress of increased lipid peroxidation. Imbalances of either EFAs or oxidation-antioxidation each have separate potential to aggravate the inflammatory process (ref.7).

The second study summarised in this issue illustrates this dilemma. Although antibiotic treatment of these patients improved their short term clinical status, these patients also had increased measures of oxidative stress which were closely correlated with rises in fatty acid levels.

Previous clinical trials have shown that giving patients antioxidant supplements can help reverse the oxidant-antioxidant imbalance and decrease lipid peroxidation (refs. 8, 9). The first study summarised above is an important addition to these trials, because it demonstrated a positive outcome not just on laboratory measures, but also on a practical clinical end point.

Other interesting features of this study were that it was medium term study (a total of 6 months of treatment), and that it found evidence of a dose-response effect. This can help us define the most appropriate dosage for such supplementation. No adverse side-effects were found.

On the other hand, the trial was still small in subject numbers. Only one of the various clinical parameters measured showed significant improvement.

There is still a lot that we have to learn about nutritional supplementation of fats and antioxidants in CF. For one thing, the assays currently used to assess lipid peroxidation and antioxidant imbalance provide only partial insights into what are very complex processes. It is far from clear how these tests relate to practical clinical outcomes, such as patient morbidity, quality of life and mortality.

There are surprisingly few clinical trials of reasonable size and duration assessing either antioxidant or EFA supplementation against such clinical outcomes (other than growth). Most of the antioxidant trials have used ß-carotene, with only a few looking at other antioxidants (such as selenium and vitamin E e.g. ref.10) We do not know with any precision how much of which antioxidants to supplement, nor for how long.

Given the critical importance of nutritional management in patients with this life-threatening disease, we can only hope that more, larger and longer clinical trials of this nature will follow.

WHAT DOES IT MEAN FOR THE CLINICIAN?

Imbalance of essential fatty acids and antioxidant deficiencies are both common in CF. Infection or increased fat intake can potentially cause tissue damage through increased lipid peroxidation, if antioxidant status is neglected.

Although there tests for `oxidative stress' are not readily available in routine clinical practice, there is some emerging evidence that antioxidant supplementation, particularly with ß-carotene, can be useful in diminishing it. Further trials are required.


References:
1. Clin Nutr 2000 Apr;19(2):79-85
2. J Pediatr 1998 Mar;132(3 Pt 1):486-92
3. Br Med Bull 1992 Oct;48(4):823-46
4. J Pediatr 1998 Mar;132(3 Pt 1):478-85
5. Acta Paediatr 1996 Dec;85(12):1426-32
6. J Pediatr Gastroenterol Nutr 2000 Oct;31(4):418-23
7. Eur Respir J 2000 Sep;16(3):534-54
8. Am J Clin Nutr 1996 Jul;64(1):87-93
9. Free Radic Biol Med 1995 May;18(5):849-59
10. Clin Chim Acta 1995 Jan 31;234(1-2):137-46


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