Selenium and hepatitis C: a treatment role
Graham Lyons B Agric Sci MPH PhD, HarvestPlus, the University of Adelaide
Introduction
Hepatitis C virus infection (HCV) poses a major public health problem globally, with over 250 million people affected. It is estimated that over 200,000 people in Australia are living with HCV, with an estimated incidence of new infections around 1,000 cases/month (Law et al, 2000).
Current drug treatments for HCV are not ideal, with high non-response and relapse rates, even with combination interferon-alpha and ribavirin therapy, especially for HCV genotypes 1 and 4 (Colombo et al, 2003; Petrenkiene et al, 2004; Puoti et al, 2004). Moreover, interferon treatment has been associated with increased risk of type 1 diabetes (Fabris et al, 2003), and anaemia is a common side-effect of combination therapy (Trivedi & Trivedi, 2004).
In view of the high prevalence and incidence rates of HCV and the relatively low effectiveness and high cost of standard treatments, the search for superior, cost-effective treatments is critical. This article discusses selenium (Se) as a potentially important component of treatment for HCV, and proposes a controlled pilot trial as a first step to evaluate the efficacy against HCV of a high-Se functional food.
Antioxidant therapy for Hepatitis C Virus Infection (HCV)
Chronic HCV is associated with low blood levels of antioxidants, including Se (Look et al, 1997a; Yu et al, 1999; Jain et al, 2002), and with high levels of oxidative stress (Jain et al, 2002; Okuda et al, 2002; Yadav et al, 2002). Therapies comprising both antioxidants alone and in combination with standard treatments have been effective against HCV. Examples include:
· In 11/23 people living with HCV refractory to interferon-alpha therapy, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were reduced by 46% and 35%, respectively, with supplementation of 800 IU/day vitamin E (von Herbay et al, 1997).
· Oxidative stress-induced liver damage was reduced by vitamin E in people living with HCV, especially in those with initial ALT levels greater than 70 IU/l (Mahmood et al, 2003).
· An interferon/antioxidant (N-acetyl cysteine 1800 mg/d; sodium selenite 400 µg/d; vitamin E 544 IU/d) combination therapy resulted in a complete response in twice as many participants with HCV as those receiving interferon only, but the difference was non-significant due to low numbers (Look et al, 1999).
· Three people with interferon-refractory HCV were reportedly living healthily and no longer require liver transplants, following therapy comprising Se (400 µg/d), vitamin E (400 IU/d), vitamin C (1500 mg/d), alpha-lipoic acid (600 mg/d) and silymarin (900 mg/d) (Berkson, 1999).
· An individual with an initial HCV viral load of 1.5 million reportedly reduced this to 200,000 (87% reduction) after 45 days of treatment with Se only (1200 µg/d), and has maintained this viral load, along with normal ALT levels, for two years with a Se supplementary intake of 300 µg/d. Another person reported a reduction in HCV viral load from 10 million to 600,000 (94% reduction) after 12 months of Se supplementation at 1000 µg/d (Konlee, 2001).
Furthermore, there is evidence that adjuvant antioxidant therapy can reduce the side-effects of standard drug therapy for HCV. For example, a tomato-based functional food high in the carotenoid, lycopene reduced ribavirin-induced anaemia (Morisco et al, 2004), and in an animal model vitamin C reduced the development of type 1 diabetes by interferon-alpha (al Zuhair & Mohamed, 1998).
On the other hand, antioxidant therapy for HCV has not always been successful. In a study of people with HCV refractory to interferon-alpha, supplementation with the glutathione precursor N-acetyl cysteine (1200 mg/d) and vitamin E (600 mg/d) did not improve the poor efficacy of retreatment with interferon-alpha alone (Ideo et al, 1999).
Although reported studies of antioxidant therapies for HCV have been small, the promising findings of most trials suggest that further studies are warranted, particularly of Se, vitamin E, alpha-lipoic acid and silymarin. It is likely that a therapy which supplies key antioxidants and naturally-occurring phytochemicals (provided by a combined oral supplement of Se, vitamin E, alpha-lipoic acid, silymarin, licorice, B vitamins and the reverse transcriptase inhibitors green tea polyphenols and Prunella vulgaris ) and also includes a healthy diet, a structured exercise program, and cessation of smoking and intake of alcohol and other drugs would provide effective and relatively inexpensive control of HCV. In the meantime, in order to determine the most efficient treatment, it is necessary to first investigate individual components. The remainder of this paper will focus on Se.
Selenium therapy for Hepatitus C Virus Infection (HCV)
Evidence for an important role for Se in treatment of HCV, in addition to that provided above, includes the following:
· Se appears to play a role in regulating RNA viral pathogenicity. In a Se-deficient environment the viruses tend to become more virulent. This has been demonstrated for HCV (Yu et al, 1999), hepatitis B (Yu et al, 1997), Coxsackie B3 (Beck et al, 1995), HIV (Baum et al, 1997; Campa et al, 1999; Baeten et al, 2001) and influenza (Beck, 2001).
· The progressive decline in Se levels characteristic of HIV infection was greater in individuals with HCV co-infection (Look et al, 1997b).
· Se appears to be protective in people living with HCV against progression to fibrosis, cirrhosis and liver cancer (Yu et al, 1999).
· A gene has been discovered in HCV that encodes glutathione peroxidase, the important antioxidant selenoenzyme (Taylor et al, 1997a; Zhang, 1999). This means that HCV requires glutathione peroxidase for normal function and will deplete Se in host cells, thus increasing oxidative stress and reducing immunocompetence. The Se-dependent glutathione peroxidase sequence is highly conserved in HCV genotype 1b, which is predominant in the USA and is one of the most prevalent genotypes in Australia. Significantly, HCV genotype 1b is associated with the highest risk of progression to fibrosis, cirrhosis and liver cancer, and poor response to interferon-alpha (Zhang, 1999).
· An HCV-encoded glutathione peroxidase gene also helps to explain HCV progression associated with oxidant stressors like alcohol and iron overload (Wenzel et al, 1993; Bonkovsky, 1997; Lieber, 2000). Se supplementation was shown to decrease high liver iron concentration in Schistosoma-infected mice (Farrag, 1999).
· Se has a role in many aspects of the immune response to infections. Se deficiency reduces immunocompetence, involving impairment of neutrophil, macrophage and polymorphonuclear leucocyte activity (Dimitrov et al, 1984; Boyne & Arthur, 1986; Spallholz et al, 1990). Se supplementation of even supposedly Se-replete individuals is immunostimulatory, and involves enhancement of natural-killer cell and lymphocyte activity as well as enhancement of proliferation of activated T-cells (Kiremidjian-Schumacher et al, 1994).
· Tobacco smoking can aggravate the histological activity of chronic HCV (Hezode et al, 2003), and Se can reduce the deleterious effects of tobacco smoking (Dilsiz et al, 1999; Duffield-Lillico et al, 2002; Klein, 2004), therefore supplementary Se may reduce the promotional effect of smoking on HCV.
In summary, the evidence suggests that, for people living with HCV who are Se-replete (i.e. with plasma Se concentration > 100 µg/l [Rayman, 2000]), oxidative stress and risk of progression to serious HCV sequelae are likely to be significantly reduced.
High-selenium wheat and selenium intake
Numerous studies have shown that nutrients and micronutrients are more beneficial when delivered in food form rather than as refined supplements. Se in wheat is mostly in the desirable selenomethionine form, is highly bioavailable, and is the most important dietary Se source for most Australian adults (Lyons et al, 2003). Biofortified high-Se wheat is a promising functional food which was effective against colon cancer precursors in an animal study (Finley & Davis, 2001).
It is likely that most Australian adults consume around 75 µg Se/day (Lyons et al, 2003). Under normal conditions, a Se intake of less than 1000 µg/day does not cause toxicity (Neve, 1991; Whanger et al, 1996). People living in parts of China, the USA, Venezuela and Greenland have ingested Se at this level for their entire lives without ill effects (Taylor, 1997b).
Baeten JM, Mostad SB, Hughes MP et al 2001. Selenium deficiency is associated with shedding of HIV-1-infected cells in the female genital tract. J Acquired Imm Defic Syndr 26(4): 360-364.
Baum MK, Shor-Posner G, Lai S 1997. High risk of HIV-related mortality is associated with selenium deficiency. J Acquired Imm Defic Syndr 15: 370-374.
Beck MA, Shi Q, Morris VC Levander OA 1995. Rapid genomic evolution of a non-virulent Coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nature Med 1: 433-436.
Beck MA 2001. Antioxidants and viral infections: host immune response and viral pathogenicity. J Am Coll Nutr 20(Suppl 5): S384-S388.
Boyne R, Arthur J 1986. The response of selenium-deficient mice to Candida albicans infection. J Nutr 116: 816-822.
Campa A, Shor-Posner G, Indacochea F 1999. Mortality risk in selenium-deficient HIV-positive children. J Acquired Imm Defic Syndr 20: 508-513.
Dimitrov N, Meyer C, Ullrey D 1984. Selenium is a metabolic modulator of phagocytosis. In Selenium in Biology and Medicine, pp. 254-262 [GF Combs, OA Levander, J Spallholz and JE Oldfield, editors]. New York: AVI Publishing.
Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF, Slate EH, Fischbach LA, Marshall JR, Clark LC 2002. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol, Biomarkers & Prev 11: 630-639.
Finley JW, Davis CD 2001. Selenium from high-selenium broccoli is utilized differently than selenite, selenate and selenomethionine, but is more effective in inhibiting colon carcinogenesis. Biofactors 14: 191-196.
Hezode C, Lonjon I, Roudot-Thoraval F, Mavier J-P, Pawlotsky J-M, Zafrani ES, Dhumeaux D 2003. Impact of smoking on histological liver lesions in chronic hepatitis C. Gut 52: 126-129.
Kiremidjian-Schumacher L, Roy M, Wishe HI et al 1994. Supplementation with selenium and human immune cell functions. Biol Trace Elem Res 41: 115-127.
Klein EA 2004. Selenium: epidemiology and basic science. J Urol 171(2 Pt 2): S50-S53.
Look MP, Rockstroh JK, Rao GS et al 1997b. Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-infection Biol Trace Elem Res 56: 31-41.
Neve J 1991. Physiological and nutritional importance of selenium. Experientia 47: 187-193.
Rayman MP 2000. The importance of selenium to human health. Lancet 356: 233-241.
Spallholz JE, Boylan LM, Larsen HS 1990. Advances in understanding selenium’s role in the immune system. Ann N Y Acad Sci 587: 123-139.
Whanger PD, Vendeland S, Park Y-C, Xia Y 1996. Metabolism of sub-toxic levels of selenium in animals and humans. Ann Clin Lab Sci 26: 99-113.
Yu SY, Zhu YJ, Li WG 1997. Protective role of selenium against hepatitis b virus and primary liver cancer in Qidong. Biol Trace Elem Res 56: 117-124.
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