Nutrients for Viral Hepatitis
Viral hepatitis (B and C) is the leading risk factor for the development of cirrhosis and liver failure. Several nutrients have been studied in human trials for their effects on minimizing risks or improving outcomes of hepatitis B viral infection, either alone or as adjuncts to antiviral drugs. These include green tea extract, selenium, coffee/chlorogenic acid, zinc, phyllanthus, whey protein, astragalus, schizandra, and milk thistle. These are reviewed in Life Extension’s Hepatitis B protocol. The nutrients S-adenosylmethionine (SAMe), N-acetyl cysteine (NAC), alpha lipoic acid, whey protein, milk thistle, licorice, schizandra, vitamin D, coffee, zinc, curcumin, and L-carnitine have each been investigated in human trials as potential adjuncts to hepatitis C treatments. See Life Extension’s Hepatitis C protocol for more details on these studies.
Nutrients for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis
In the United States and developing world, NAFLD and NASH together are the third most common cause of cirrhosis. Vitamin E, omega-3 fatty acids, and N-acetyl cysteine plus metformin have each been studied as possible adjuncts to treatment of NAFLD and NASH in human trials.
Further nutritional strategies are reviewed in Life Extension’s Non-Alcoholic Fatty Liver Disease (NAFLD) protocol.
Nutrients for Iron Overload
High iron stores are a risk factor for the development of liver disease (Fargion 2011; Valenti 2012), and patients with hereditary hemochromatosis are at increased risk for cirrhosis (Crownover 2013). Nutrients that have been investigated in human clinical trials for their ability to reduce iron load include pectin, milk thistle, and green tea (reviewed in Life Extension’s Hemochromatosis protocol).
Nutrients specifically investigated in the context of cirrhosis or its complications include:
Milk thistle and its principal flavonoid mixture silymarin have shown remarkable hepatoprotective and antioxidant effects against several types of liver damage (including chemical, viral, inflammatory, and poisoning) in laboratory, rodent, and human settings (Vargas-Mendoza 2014; Polyak 2013; Jia 2001). They have been investigated for a number of chronic liver conditions that can precede cirrhosis, including viral hepatitis (Hawke 2010), alcoholic liver disease (Habib-ur-Rehman 2009; Ferenci 1989), and NAFLD (Loguercio 2012). Studies in cirrhotic patients have shown mixed results. In a study of patients with alcoholic and non-alcoholic cirrhosis, 4-year survival rates were higher in patients on silymarin (140 mg, three times daily) compared to control subjects (58% vs. 39%, respectively) (Ferenci 1989). A similar study, however, failed to show any survival benefit at 6 years in patients taking 450 mg silymarin per day. It is important to note that all the patients in this second study had alcoholic cirrhosis, and many significantly reduced their alcohol intake over the course of the study, possibly obscuring any effects of silymarin (Parés 1998). In patients with alcoholic cirrhosis, silymarin reduced markers of oxidative damage and improved antioxidant status (Lucena 2002).
Branched-Chain Amino Acids
Branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine), nutritionally essential amino acids not metabolized into energy in the liver, are taken up by skeletal muscle where they serve multiple purposes. The breakdown products of BCAAs can be used to form the amino acid glutamate, which can scavenge toxic ammonia in skeletal muscles and convert it into glutamine (Dam, Ott 2013; Amodio 2013). A systematic review of 8 trials (382 cirrhosis patients) on the use of BCAAs for symptoms of hepatic encephalopathy demonstrated a clear benefit in reducing manifestations of the disease in patients with both minimal and overt forms of encephalopathy (Gluud 2013). The effect was independent of the cause of cirrhosis (alcoholic or viral), and the average dose was 0.25g/kg/day. Other authors believe that the effect of BCAAs is entirely a result of their leucine content, and that while BCAAs may eventually be proven to have nutritional benefits for cirrhosis patients, including regeneration of liver cells, they are not effective for hepatic encephalopathy (Amodio 2013).
About 66% of patients with moderately severe cirrhosis, and 96% of people waiting for liver transplants, have vitamin D deficiency. In individuals with chronic liver disease, the rate of osteoporotic fractures is approximately twice that of age-matched controls. For these reasons, calcium and vitamin D supplementation have been recommended for patients with cirrhosis and low bone density (Crawford 2006). In a study of over 324 subjects with alcoholic liver disease compared to controls, severe vitamin D deficiency was significantly associated with higher liver enzymes, increased hepatic venous pressure gradient, and worse MELD and Child-Pugh scores. Further analysis showed that low vitamin D was associated with cirrhosis and mortality after one year (Trepo 2013). An analysis of chronic liver disease patients admitted to an outpatient liver clinic found that vitamin D deficiency predicted worse Child-Pugh and MELD scores, and may predict decompensation and mortality in chronic liver failure patients (Putz-Bankuti 2012). A study on 88 hospitalized patients in the hepatology unit of a hospital revealed that low levels of vitamin D were independently associated with bacterial infection in patients with cirrhosis; another similar study found that low vitamin D was associated with increased mortality in patients with severe liver disease (Anty 2014; Stokes 2013). A laboratory study using a special form of vitamin D along with a novel chemotherapeutic agent inhibited proliferation of hepatic stellate cells (Neeman 2014).
Patients with cirrhosis show endothelial dysfunction within the vessels of the liver, and this is associated with lower circulating levels of vitamin C. In an uncontrolled study of cirrhosis patients, intravenous injection of 3 g vitamin C lowered markers of oxidative stress and venous pressure within the liver (Hernández-Guerra 2006). Vitamin C mitigated the increase in liver fat and globulins (blood proteins) caused by experimentally induced cholestasis (decreased bile flow) in rats (Matos 2008) and reduced alcohol-induced small-intestinal bacterial overgrowth in a model of alcoholic liver fibrosis in guinea pigs (Abhilash 2014).
Liver cirrhosis patients generally have low blood levels of vitamin E; liver biopsies from people with alcoholic cirrhosis typically show lower hepatic alpha-tocopherol content than individuals with normal livers, and lower blood alpha-tocopherol levels than individuals with alcoholic fatty liver or those with normal liver histology (Bell 1992; Lu 2003). These lower levels of vitamin E were associated with an increased susceptibility of the plasma component of blood to oxidative stress (Ferre 2002; Lu 2003). In patients with primary biliary cirrhosis, one author concluded that vitamin E supplementation should be considered not only in individuals with overt vitamin E deficiency, but also in individuals who meet certain additional criteria, such as total serum bilirubin over 3 mg/dL, serum cholylglycine (a crystalline bile acid involved in emulsification of fat) over 600 mcg/dL, or serum alkaline phosphatase over 1000 IU/L (Sokol 1989). In a study that enrolled women with primary biliary cirrhosis, serum vitamin E levels were significantly decreased in patients who had psychomotor impairment (Arria 1990).
Patients with liver cirrhosis show marked increases in oxidative stress levels. In patients with hepatitis C-related cirrhosis, vitamin E normalized levels of the liver enzyme alanine aminotransferase (ALT), while vitamin E and fermented papaya extract each improved glutathione levels, which were significantly lower in patients with cirrhosis (Marotta 2007). A study on patients with liver cirrhosis and a history of hepatitis C infection revealed that participants treated with alpha-tocopherol lived longer without the development of hepatocellular carcinoma as compared to participants who were not treated, but the difference was not statistically significant (Takagi 2003). A study on 80 prospective liver transplantation recipients showed that oral tocotrienols lowered MELD scores by 50%, whereas supplementation with 200 mg alpha-tocopherol lowered it by only 20%. The authors concluded that further studies are needed to examine the effects of tocotrienols in end-stage liver disease (Patel 2012).
The wrong kind of intestinal bacteria play a role in several complications of cirrhosis; urease-producing bacteria in the gut increase ammonia production, which contributes to hepatic encephalopathy, and migration of bacteria across the intestinal wall has been implicated in both spontaneous bacterial peritonitis and bleeding due to esophageal varices (Pereg 2011). Use of probiotics to address these complications has had mixed results. In some studies, supplementation of cirrhosis patients with probiotic bacteria (including species of Lactobacilli, Bifidobacteria, Pediococcus, and Leuconostoc) combined with fermentable fiber prebiotics reduced blood ammonia levels and urease-producing colonic bacteria (Malaguarnera 2010; Liu 2004). Two studies that used a slightly different combination of probiotics without prebiotics found no effect (Saji 2011; Pereg 2011). There was a trend toward reduced Child-Pugh scores (suggesting an improvement in liver function) in some studies (Lata 2007; Liu 2004), mixed results on portal venous pressure (Gupta 2013; Tandon 2009), and no reduction in the incidence of spontaneous bacterial peritonitis (Pande 2012).
Hepatic encephalopathy, a complication of cirrhosis, is currently treated by the nondigestible, fermentable disaccharide lactulose, a synthetic prebiotic (Wang 2013; Amodio 2013). Combinations of fermentable natural fibers (beta-glucan, inulin, pectin, and resistant starch) (Liu 2004) or fructooligosaccharides (Malaguarnera 2010) with probiotic bacteria showed reductions in blood ammonia levels in cirrhosis patients with minimal or mild hepatic encephalopathy.
In a meta-analysis of 4 randomized controlled trials of oral zinc supplementation (zinc acetate, sulfate, or carnosate) in 223 patients with hepatic encephalopathy resulting from cirrhosis, three trials showed improvements in cognitive function compared to baseline measurements (Chavez-Tapia 2013). In the fourth study using zinc carnosate, cirrhosis patients experienced reductions in blood ammonia levels, improved quality of life scores, and reduced Child-Pugh scores (measurements of cirrhosis severity) after six months of supplementation.
S-adenosylmethionine (SAMe) participates in the synthesis of the important liver-protectant antioxidant glutathione, which is lower in patients with cirrhosis (Bianchi 1997; Mato 1999). Although SAMe has been studied as an innovative therapy for fibrosis (Czaja 2014), one systematic review of the literature was unable to confirm a statistically significant benefit in alcoholic liver disease, perhaps partially as a result of variable quality across studies (Rambaldi 2006). In a large clinical trial of SAMe (Mato 1999), patients with alcoholic cirrhosis on SAMe (1.2 g/day for 2 years) demonstrated a non-significant trend towards improvement in 2-year survival compared to control patients. When only patients with mild-to-moderate disease were included in the analysis, however, survival was significantly improved, and progression to liver transplantation was significantly reduced in the SAMe group (88%) versus the control group (71%). Differences in survival between the groups only became apparent after 1 year. Many of the subjects in this trial had hepatitis B or C infection in addition to alcoholic cirrhosis. While several other smaller studies have shown encouraging results for the use of SAMe to improve liver biochemical parameters (such as liver enzyme values) in alcoholic cirrhosis patients, they have shown mixed results for its ability to improve survival in patients with the disease and have had no apparent effect on steatosis, fibrosis, or inflammation (Rambaldi 2006; Medici 2011; Le 2013).
Soybeans contain a lipid mixture called polyenylphosphatidylcholine (PPC) that has been shown to help protect the integrity of cellular membranes, especially in the liver. One of the mechanisms by which toxicants like alcohol lead to liver dysfunction is by damaging liver cell membranes in a process called lipid peroxidation. PPC helps prevent lipid peroxidation in liver cells. The lipid mixture prevented cirrhosis in animal experiments, and it opposed fibrosis and improved liver function tests among heavy-drinking human clinical trial participants (Lieber 2004; Lieber 2003).
In animal models, curcumin has mitigated liver injury from hepatitis B and C infection, alcoholic liver disease, NAFLD, hepatocellular carcinoma, primary biliary cirrhosis, and primary sclerosing cholangitis; all chronic liver diseases with cirrhosis as their potential endpoint (Nabavi 2013). It may also have a protective effect against chemically-induced cirrhosis in animal livers (Ali 2014). In these models, curcumin inhibits metabolic pathways (such as NF-κB signaling) that produce the inflammatory cytokines that stimulate fibrosis (Nabavi 2013). In addition, laboratory and animal studies have shown that curcumin reduces β-catenin, a protein that promotes liver stellate cell activation and fibrosis (Cui 2014).
Glycyrrhizic acid, also known as glycyrrhizin, is an extract from the roots of the licorice plant Glycyrrhiza glabra. It has been studied and found effective in many conditions (Li 2014), but its most common application is in liver disease, where it has pronounced anti-inflammatory (Ming 2013) and anti-viral (Pu 2013) effects.
A trial compared intravenous (IV) glycyrrhizic acid in 17 patients to IV glycyrrhizic acid plus corticosteroids in 14 patients for the treatment of autoimmune hepatitis. Recovery rate was significantly higher in the glycyrrhizic acid alone group (Yasui 2011). A trial in 379 patients who failed interferon plus ribavirin treatment for hepatitis C found that a twelve-week course of IV glycyrrhizic acid, compared to placebo, dramatically lowered the liver enzyme ALT. A subsequent 40-week uncontrolled trial of IV glycyrrhizic acid found a trend towards reduction of inflammation and fibrosis that barely missed the cutoff for statistical significance (Manns 2012). An uncontrolled study of long-term (average 10 years) oral glycyrrhizic acid administration in hepatitis C found that those in the treatment group had 2.5 times less chance of developing hepatocellular carcinoma, a common outcome of hepatitis C (Arase 1997). In a rodent model, glycyrrhizic acid was found to have hepatoprotective effects similar to silymarin (Rasool 2014).
Coenzyme Q10 (CoQ10) acts as a scavenger of free radicals in cell membranes. One study found that CoQ10 levels were 70% lower in subjects with liver cirrhosis compared to healthy controls; the authors speculated that this may be a result of low dietary intake of this important nutrient, or due to decreased synthesis in the cells (Bianchi 1994). Reduced CoQ10 levels are also seen in patients with NAFLD (Yesilova 2005). CoQ10 (10 or 30 mg/kg) inhibited fibrosis induced by the liver toxin dimethylnitrosamine in mice (Choi 2009).
Berberine is a plant alkaloid that has been studied primarily for its bacteriostatic and bactericidal properties (Sun 1988). In patients with hepatic encephalopathy, oral berberine (600-800 mg/day) reduced blood concentrations of tyramine, an indirect neurotransmitter that is elevated in hepatic encephalopathy and can lead to some of its cardiovascular and neurological complications (Watanabe 1982). In a small trial of patients with chronic hepatitis B, C, or cirrhosis, berberine (1 g/day for 3 months) reduced circulating LDL and total cholesterol levels and liver enzymes (Zhao 2008).
Although berberine has been studied in human clinical trials and shown to have several metabolic benefits, concerns about long-term use of berberine have been raised on the basis of certain preclinical studies (Kysenius 2014; Mikes 1985; Mikes 1983). Some evidence suggests that long-term berberine use, especially at high doses, may impair particular aspects of cellular metabolism in specific types of cells. The implications of this preclinical research are yet to be determined by long-term human clinical trials, therefore Life Extension currently recommends short-term use of berberine.
Green Tea Extract/Epigallocatechin-3-gallate
Epigallocatechin-3-gallate (EGCG) is the most potent and abundant catechin in green tea extract, usually comprising approximately 40% of green tea’s polyphenol content. The anti-inflammatory, antioxidant, and anti-fibrotic properties of EGCG make it a candidate as a natural therapy for hepatitis and liver fibrosis (Halegoua-De Marzio 2012). In a laboratory study, EGCG inhibited entry of the HCV into liver cells (Ciesek 2011). An experiment with hepatic stellate cells, which are key in the development of liver fibrosis, revealed that EGCG can regulate the growth and structure of these cells, such that EGCG may turn out to be a therapeutic agent for liver fibrosis (Higashi, Kohjima 2005). In a rat model of NASH, which is characterized by liver inflammation and fibrosis, and is associated with liver cancer, oral administration of EGCG (0.1% in tap water) was shown to prevent liver fibrosis and tumorigenesis (Kochi 2014). In a mouse model of chemically-induced liver injury and fibrosis, EGCG was able to attenuate the progression of liver fibrosis, possibly as a result of its ability to reduce oxidative stress and inflammatory response (Tipoe 2010).
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