Effects of glutathione, α-lipoic acid, and N-acetylcysteine on recovery from the malnutrition syndrome kwashiorkor
Malnutrition represents one of the most severe socioeconomic and health problems in the world. In many African countries kwashiorkor, a severe edematous form of malnutrition in childhood, has a high prevalence and mortality. The pathophysiology of the syndrome is poorly understood and its clinical management is still insufficient.
The full clinical picture of kwashiorkor includes skin lesions, red hair discoloration and partial loss of hair, fatty liver, apathy, and irritability. The syndrome is typically precipitated by infections and has for many years been considered to be based on protein deficiency. However over the last decade, a role of oxidative stress in the pathophysiology of kwashiorkor has emerged. The syndrome is associated with decreased concentrations of the cysteine-containing antioxidant glutathione, with low concentrations of vitamin E, carotene, selenium, and polyunsaturated fatty acids; with a reduced NADPH/NADP+ ratio; and with low glutathione peroxidase and elevated glutathione S-transferase activity. Furthermore high concentrations of circulating ferritin and hepatic iron have been reported as signs of liver injury, and biomarkers of oxidant-induced lipid peroxidation such as malondialdehyde, hexanal, and lipid hydroperoxide have been found to be elevated in the patients. In a recent study the plasma total antioxidant status (TAOS) of kwashiorkor patients was shown to be reduced to less than 50% of local control values, whereas the concentrations of the nitric oxide metabolites nitrite and nitrate were increased by a factor of 2.
As repeatedly described, the erythrocyte glutathione (γ-glutamyl-cyteinyl-glycine; GSH) concentration is drastically reduced in kwashiorkor, and this has been related to the clinical outcome of the syndrome. In fact over an observation period of 20 days, glutathione levels rose in patients who recovered but decreased or were constant in those patients who did not. Apart from the multiple functions of glutathione in the cellular redox equilibrium – it is inter alia able to react directly with reactive oxygen species and is a cosubstrate of the enzyme glutathione-peroxidase – its beneficial effects on cell membrane electrolyte transport might play an important role in the pathophysiology of kwashiorkor. As demonstrated by Forrester et al., reduction of the intracellular glutathione content of normal red cells to values characteristic for edematous malnutrition reproduced the abnormalities of sodium content and sodium fluxes observed in kwashiorkor. As discussed in the context of a previous study, NO might contribute to the reduced glutathione levels in many cell types by directly reacting with glutathione or by inhibiting antioxidant enzymes such as glutathione reductase. A vicious cycle would develop since glutathione plays a crucial role in protecting from NO-induced cytotoxicity. Additionally, GSH depletion and increased iron concentrations do facilitate the induction of inducible NO-synthase.
Taken together, the available data strongly suggest that glutathione deficiency plays a key role in the pathogenesis of kwashiorkor. This deficiency is likely to result from both oxidative stress followed by increased GSH-loss and from impaired GSH-synthesis due to cysteine deficiency. Therefore cysteine-containing compounds restoring the cellular capacity to synthesize GSH or antioxidant compounds mimicking the functions of GSH were suggested to be beneficial for recovery from kwashiorkor. And indeed, as recently reported by Badaloo et al., early dietary supplementation with cysteine – applied as N-acetlycysteine – significantly increased the glutathione concentration and synthesis rate along with erythrocyte cysteine concentrations in kwashiorkor patients.
In the longitudinal clinical trial reported here, we tested the hypothesis that the cysteine donors glutathione and N-acetylcysteine and the dithiol antioxidant α-lipoic acid, respectively, increase glutathione concentrations and are beneficial for the clinical recovery of kwashiorkor patients.
Objective: We tested the hypothesis that oral application of thiol-containing antioxidants increases glutathione status and is beneficial for the clinical recovery of kwashiorkor patients.
Design: In a longitudinal clinical intervention study carried out at St. Joseph's Hospital in Jirapa, Ghana, children with severe kwashiorkor were randomly assigned to either a standard treatment (ST) receiving a therapeutic protocol based on the recommendations of the WHO or to one of 3 study groups receiving in addition 2 x 600 mg reduced α-lipoic acid (LA), and 2 x 100 mg glutathione (G), 2 x 50 mg N-acetylcysteine (ACC) per day, respectively. Patients were followed up clinically and biochemically for 20 days and compared with 37 healthy controls.
Results: As based on statistical analyses, both glutathione and α-lipoic acid supplementation have a strong and positive effect on survival. Also the blood glutathione concentrations of the patients have a significant positive effect on the survival rates. Furthermore, the initial skin lesions, glutathione, and total protein concentrations were found to be strong predictors of survival.
Conclusions: The data strongly suggest that a therapy restoring the antioxidative capacity by applying cysteine equivalents in the form of glutathione is beneficial for biochemical and clinical recovery of kwashiorkor patients.
Becker K, Pons-Kühnemann J, Fechner A, Funk M, Gromer S, Groß HJ, Grünert A & Schirmer RH (2005). Effects of antioxidants on glutathione levels and the recovery from the malnutrition syndrome kwashiorkor: a pilot study. Redox Report 10: 215-226.