Targeted Natural Therapeutics
Boosting Liver Glutathione and Easing Oxidative Stress
Glutathione acts as a cellular detoxifier and helps prevent damage from free radicals (Cacciatore 2010). However, glutathione depletion is a common finding among HCV-infected patients (Tapryal 2010). The following compounds may help to increase glutathione levels.
N-acetyl-cysteine. N-acetyl-cysteine (NAC) is derived from L-cysteine, a conditionally essential amino acid. This powerful antioxidant diminishes free radicals and raises glutathione levels (Nguyen-Khac 2011). In conventional medicine, NAC has been used to treat acetaminophen poisoning. In children with acute liver failure from causes other than acetaminophen poisoning, receiving NAC was associated with a shorter hospital stay, greater incidence of liver recovery, and better survival after transplantation (Kortsalioudaki 2008). In an early trial, addition of NAC to interferon boosted glutathione levels in white blood cells of patients with chronic hepatitis C and normalized ALT levels in 41% of interferon non-responders (Beloqui 1993). While more recent trials have been unable to confirm the therapeutic role of NAC in chronic hepatitis C, they have established it is very well tolerated (Grant 2000; Gunduz 2003).
S-adenosyl-L-methionine. S-adenosyl-L-methionine (SAMe), a methyl donor for numerous methylation reactions, has been studied for its antidepressant properties (Nahas 2011). SAMe also regulates glutathione synthesis (Medici 2011). In HCV-infected patients who were non-responders to previous antiviral therapy, adding SAMe to a pegylated interferon plus ribavirin (PEG-IFN/RBV) regimen improved early viral response (Feld 2011). In a separate trial, SAMe and trimethyglycine (another methyl donor) were given along with pegylated interferon plus ribavirin to chronic hepatitis C patients. The treatment resulted in an early virological response (EVR) in 59% of subjects, whereas pegylated interferon plus ribavirin alone had previously achieved only a 14% EVR (Filipowicz 2010).
Lipoic acid. This free-radical scavenger helps to repair damage caused by oxidative stress, assisting in the regeneration of important antioxidants such as glutathione and vitamin E (Shay 2009). In animals, lipoic acid has been found to prevent fatty liver disease (Park 2008). In human trials, administration of antioxidant blends containing lipoic acid was shown to favorably modulate liver enzymes, HCV RNA levels, and liver biopsy score in HCV patients (Melhem 2005; Berkson 1999).
Whey protein. Whey protein boosts glutathione levels and improves the functioning of the immune system (El-Attar 2009). In an animal model of hepatitis, whey protein supplementation attenuated chemical-induced liver enzyme elevations (Kume 2006). Moreover, a clinical study found oral whey protein reduced viral load, decreased inflammation, lowered ALT levels, and exerted other beneficial effects in compensated chronic HCV-infected patients (El-Attar 2009).
Selenium. Selenium is an essential component of glutathione peroxidase, an enzyme that protects cells from free radical damage (Khan 2012). Patients with hepatitis C or B have been found to have lower serum selenium concentrations than healthy individuals (Khan 2012). Moreover, selenium deficiency is thought to contribute to insulin resistance in people with HCV-related chronic liver disease; and reduced selenium levels have been observed in patients with hepatocellular carcinoma (Rohr-Udilova 2012; Himoto 2011).
Glutathione. A 1989 study found consumption of oral glutathione increased plasma glutathione levels (Jones 1989). Preclinical trials found oral glutathione increases glutathione levels in tissues such as the lungs, liver, and kidneys (Hagen 1990; Kariya 2007; Aw 1991; Iantomasi 1997; Favilli 1997).
Targeting Excess Iron Levels
Lactoferrin. Lactoferrin, an iron-binding glycoprotein, may be beneficial as an adjunctive treatment for serum iron overload in hepatitis patients. Lactoferrin is a potent antioxidant, antiviral agent, and scavenger of free iron (Actor 2009). In addition, it is directly involved in the upregulation of natural killer cell activity, making it a natural mediator of immune function (Actor 2009). As an immune mediator, lactoferrin may work synergistically with interferon to reduce viral load (Ishii 2003). In another study among patients with chronic HCV, lactoferrin alone significantly lowered the HCV RNA titer and improved efficacy of subsequent treatment with interferon and ribavirin (Kaito 2007).
Green Tea. Epigallocatechin-3-gallate (EGCG) from green tea has been found to interrupt the first step of HCV infection by blocking the virus from entering target cells. In addition, EGCG inhibited cell-to-cell transmission of HCV. Both of these effects were observed regardless of the genotype tested. These findings carry important implications for the prevention of HCV re-infection in liver transplant patients (Ciesek 2011). In addition, green tea has been shown to inhibit iron absorption in intestinal cells (Ma 2011) and accumulation in liver tissue (Saewong 2010), which can contribute to excessive oxidative stress.
Elemental Calcium. Calcium inhibits iron absorption (Shawki 2010). Taking 600 mg of elemental calcium can reduce iron absorption by as much as 60% (Hallberg 1991).
Additional Natural Liver Protection
Milk Thistle. Silymarin and its chief active ingredient, silibinin, are derived from milk thistle, a member of the daisy family. Both substances help the liver avoid toxic damage and regenerate after injury.
Findings from several studies suggest silymarin has potential antiviral (Polyak 2007), antioxidant (Bonifaz 2009), anti-inﬂammatory (Polyak 2007; Morishima 2010), and antiﬁbrotic (El-Lakkany 2012) effects within the liver. It may also improve liver enzyme levels in HCV patients (Mayer 2005).
In a recent cell culture study, silymarin inhibited entry of HCV into cells, inhibited viral RNA and protein expression, and decreased cell-to-cell transmission of HCV (Wagoner 2010).
A clinical study involving 1,145 HCV-infected participants showed patients using silymarin had fewer liver-related symptoms and somewhat higher quality-of-life scores (Seeff 2008). Doses greater than 700 mg may improve bioavailability of silymarin; and oral doses of up to 2.1 g per day have been found to be safe and well tolerated (Hawke 2010).
The antioxidant, antifibrotic, and metabolic effects of silibinin have been demonstrated in numerous studies (Loguercio 2011; Trappoliere 2009). Silibinin also has antiviral capabilities (Ahmed-Belkacem 2010; Ferenci 2008).
The clinical efficacy of oral silibinin in active chronic hepatitis C has not yet been clearly established (Loguercio 2011; Verma 2007). However, intravenous silibinin effectively treated HCV re-infection following liver transplantation in a small number of patients in one trial (Eurich 2011), and helped 85% of non-responders to standard of care achieve undetectable HCV RNA levels in another (Rutter 2011). Likewise, administering high doses of silibinin intravenously in addition to pegylated interferon plus ribavirin therapy lowered viral loads in HCV-infected patients who were previous non-responders to treatment (Ferenci 2008); and 1,400 mg of intravenous silibinin daily for 14 days successfully induced sustained virologic response (SVR) in a 57-year-old liver transplant patient (Neumann 2010).
A medical literature review found no significant side effects with silybin phytosome at doses up to 10 grams per day, and no significant interactions with other medications (Loguercio 2011).
Polyenylphosphatidylcholine. Polyenylphosphatidylcholine (PPC) is a major component of essential phospholipids (Okiyama 2009). In addition to improving liver enzymes in HCV (Singal 2011), PPC replenishes levels of S-adenosyl-L-methionine (SAMe), a precursor to the potent antioxidant glutathione (Lieber 2005). PPC protects against liver damage (Okiyama 2009) and improves liver function (Zhao 2011; Singal 2011). In animal studies, it has demonstrated antioxidant, cytoprotective, anti-inflammatory, and antifibrotic effects, inhibiting oxidative stress and the development of alcoholic liver disease (Okiyama 2009; Singal 2011). Numerous double blind, placebo-controlled clinical trials have shown essential phospholipids improve chronic hepatitis among human subjects (Gundermann 2011).
Schisandra chinensis. Berries from the Schisandra chinensis (S. chinensis) plant contain active ingredients that protect the liver (Azzam 2007). Crude schisandra and its extracts have traditionally held a role in Chinese and Japanese medicine (Azzam 2007), and S. chinensis has been used to treat chemical and viral hepatitis (Chien 2011). A study examining the effects of a Japanese herbal combination containing S. chinensis indicated Schisandra fruit could inhibit HCV infection (Cyong 2000). The seed extract from S. chinensis appears to have liver-detoxifying capabilities; components of the seed extract are thought to have anticancer, anti-inflammatory, liver-protective, anti-HIV, and immunomodulating effects (Wang 2007).
Licorice Root Extract. Licorice root extract (glycyrrhizin) is known to exert an antiviral effect against HCV (Ashfaq 2011). In Japanese HCV patients, the long-term use of glycyrrhizin has shown to be helpful in preventing inflammation, liver cirrhosis, and hepatocellular carcinoma (Guyton 2002; Kumada 2002). The broad anti-inflammatory activity (Schröfelbauer 2009) and antioxidant capabilities (Li 2011) of glycyrrhizin have also been observed. Adding a nutritional supplement containing vitamin C, glycyrrhizic acid, and other antioxidants to standard pegylated interferon plus ribavirin treatment has been linked to a notably higher rate of biochemical and histologic improvements in patients with chronic HCV (Gomez 2010; Vilar Gomez 2007). In chronic HCV patients, oxidative stress and immunological parameters showed marked improvement following treatment with this blend (Gomez 2010).
A preparation known as Stronger Neo-Minophagen C (SNMC) contains glycyrrhizin as an active component and has been used in Japan for more than 30 years to treat chronic hepatitis (Kumada 2002). In animals with HCV, SNMC has been found to prevent fatty liver disease (Korenaga 2011) and protect liver cells against carbon tetrachloride-induced oxidative stress by restoring depleted glutathione levels (Hidaka 2007). A possible side effect associated with ingestion of large amounts of licorice is hypertension (Nielsen 2012); therefore, blood pressure should be monitored regularly.
Vitamin D. Diminished vitamin D levels have been observed in HCV patients (Arteh 2010; Petta 2010). Low serum vitamin D levels are associated with severe fibrosis, as well as a low sustained virological response to pegylated interferon plus ribavirin treatment in patients with chronic HCV infection (Petta 2010); and vitamin D supplementation has been found to enhance HCV response to pegylated interferon plus ribavirin therapy (Abu-Mouch 2011). In a recent study involving patients with HCV genotype 2-3 receiving pegylated interferon plus ribavirin treatment, supplementing with oral vitamin D significantly improved viral response. Twenty-four weeks after treatment, 95% of the treatment (vitamin D) group was HCV RNA negative versus 77% of the control group (Nimer 2012).
Coffee. A recent study showed patients with advanced HCV-related chronic liver disease who drank 3 or more cups of coffee each day were about 3 times more likely to respond to pegylated interferon plus ribavirin treatment than non-drinkers. These patients were previous non-responders to interferon treatment (Freedman 2011). Published study reports have documented an association between coffee consumption and lowered risks of liver cirrhosis (Modi 2010; Klatsky 2006), hepatocellular carcinoma (Larsson 2007; Bravi 2007), liver disease progression in HCV infection (Freedman 2009), and lower serum ALT activity (Ruhl 2005a). Population studies have shown coffee drinking reduces the risk of clinically significant chronic liver disease (Ruhl 2005b). These effects may be due in part to the antiviral activity of chlorogenic acid, a coffee polyphenol found in especially high concentrations in green coffee extracts (Wang 2009).
Zinc and zinc-carnosine. Zinc has HCV-inhibiting capabilities (Yuasa 2006). Zinc supplementation has resulted in a higher reported rate of HCV eradication among patients receiving interferon treatment (Takagi 2001), decreased gastrointestinal disturbances and hair loss, and improved fingernail health in patients with chronic HCV. It may also improve patient tolerance to IFN-alpha-2a and ribavirin (Ko 2005b).
A chelate compound consisting of zinc and L-carnosine may induce anti-oxidative functions in the liver, thereby decreasing liver cell injury (Murakami 2007). Supplementation with chelated zinc-carnosine has been found to lessen the degree of liver damage and improve long-term outcome of patients with chronic HCV infection or liver cirrhosis (Matsuoka 2009). In patients with HCV-related chronic liver disease, it appears to have a beneficial anti-inflammatory effect on the liver by decreasing iron overload (Himoto 2007). In addition, fewer gastrointestinal side effects were observed when zinc-carnosine supplementation was added to combination pegylated interferon plus ribavirin therapy (Suzuki 2006).
Curcumin. Curcumin is a yellow pigment present in the curry spice turmeric. It possesses antioxidant, anti-inflammatory, anti-fungal, antibacterial, and anti-proliferative capabilities (Aggarwal 2003; Rahman 2006; Aggarwal 2007). In addition, curcumin has been found to exert antiviral activity against a variety of viruses including the human immunodeficiency virus (HIV) (Li 1993), influenza virus (Chen 2010), and coxsackievirus (Si 2007). One team of researchers found curcumin reduces HCV gene expression, and combining curcumin with IFN-alfa treatment had "profound inhibitory effects" on HCV replication. The authors concluded curcumin may be valuable as a novel anti-HCV agent (Kim 2010). Curcumin has also been shown to protect against liver cancer (Darvesh 2012).
Quercetin. Quercetin is a flavonoid present in fruit, vegetables, wine, and tea that has antioxidant and anti-inflammatory properties. Studies indicate it also possesses anti-hypertensive, anti-bacterial, anti-fibrotic, anti-atherogenic, and anti-proliferative properties (Boots 2008). Quercetin has also been found to attenuate HCV virus production (Gonzalez 2009; Bachmetov 2012).
L-carnitine. Chronic HCV patients received pegylated interferon plus ribavirin plus the amino acid L-carnitine or pegylated interferon plus ribavirin alone for 12 months. A significant improvement in sustained virologic response was observed in 50% of the L-carnitine group versus 25% of the non-L-carnitine group (Malaguarnera 2011a). Supplementing pegylated interferon plus ribavirin treatment with L-carnitine has also been associated with decreased mental and physical fatigue, as well as improved health-related quality of life in patients with chronic HCV. These latter outcomes could potentially improve patient compliance with pegylated interferon plus ribavirin treatment (Malaguarnera 2011b).