Natural compounds to protect the liver

An array of dietary supplements provide strong support for the liver, protecting against damaging exposures — not the least of which are some of the newer pharmaceuticals, like statin drugs. Conrad Earnest, PhD, investigates the research behind the best evidence-based supplements and botanicals

An examination of dietary supplements that affect liver function is a daunting task. Characteristically, the liver performs a vital role in regulating, synthesising, storing, secreting, transforming and breaking down many different substances in the body. In addition, the liver?s ability to regenerate lost tissue helps maintain these functions, even in the face of moderate damage.

In brief, liver functions are divided into three basic categories: regulation, synthesis and secretion of substances important to bodily homeostasis. This includes storage of nutrients such as glycogen; vitamins and minerals; and the purification, transformation and clearance of waste products, drugs and toxins. Disease, injury and toxic insult greatly reduce the liver?s ability to carry out these activities. Most of the clinical manifestations of liver dysfunction stem from cell damage and impairment of liver capacities.

Equally confusing from a product standpoint is ubiquitous terminology such as ?detoxification,? which is a global descriptor rather than one that describes a specific function. The aim of this article is to focus on nutrients that affect specific parameters of liver function. Readers are advised, however, that the overwhelming bulk of scientific literature focuses on animal research and areas of human disease and toxicity. Thus, applications involving an attempt at prophylaxis should be treated with some caution.

Milk Thistle/Silymarin
Milk thistle has been used as an herbal remedy for many years. The active extract of milk thistle is silymarin, a mixture of the flavonolignans, silydianin, silychristine and silybin. The latter component is thought to be the most biologically active. Silymarin concentrations are highest in the fruit of the plant, from which it is typically extracted. Oral doses peak in the bloodstream after about two hours. Half-time elimination takes place after about six hours.

Many studies have demonstrated the beneficial hepatoprotective effects of treatment with silymarin. For example, patients with elevated serum liver enzymes primarily from alcohol ingestion who consumed 420mg/day silymarin were able to significantly lower the liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT) — after four weeks. Elevated concentrations of AST and ALT are used to screen for liver damage from disease or drugs.1

A longer trial involving patients with liver cirrhosis also consuming 420mg/day of silymarin for an average of 41 months resulted in improved survival (58 per cent silymarin vs 39 per cent in the placebo.)2 However, improvements in mortality are not always the case as a study involving 116 patients with histologically proven alcoholic hepatitis demonstrated no significant alteration in the course of the disease.3

Silymarin has been reported to protect liver cells from a wide variety of toxins, including acetaminophen, ethanol and D-galactosamine
Silymarin also has been reported to protect liver cells from a wide variety of toxins, including acetaminophen, ethanol, carbon tetrachloride and D-galactosamine. 4,5,6,7,8 The mechanisms providing silymarin?s hepatoprotective effects are many and varied. They include antioxidation, anti-lipid peroxidation and protection against glutathione depletion. Silymarin also protects liver cells from ischemic injury and iron toxicity. 4,9,10,11,12,13,14,15,16,17 One of the most interesting mechanisms of action pertaining to silymarin is the ability to regenerate hepatic tissue by increasing the formation of ribosomes, DNA and protein synthesis. 18

N-acetyl-cysteine (NAC) is a precursor of reduced glutathione (GSH). Glutathione is an antioxidant containing the amino acid cysteine, which is needed for cellular production of energy and proper immune function. In addition to its mucolytic (dissolving) action, NAC is utilized in conditions of decreased GSH or oxidative stress. Its most notable use, however, is the hepato-protective effect that NAC exerts in cases of acetaminophen poisoning.

Following an oral dose, NAC is rapidly absorbed and peaks in the plasma in less than one hour. The plasma half-life of NAC is estimated to be about 2.15 hours.19,20 However, due to the extensive first pass metabolism by cells of the small intestine and the liver, only a small percentage of the intact NAC molecule arrives in the plasma and tissue.20

The majority of beneficial effects from NAC are theorized to be a result of either the reduction of extracellular cystine to cysteine, or as a source of sulfhydryl (sulfur and hydrogen containing) metabolites. As a source of sulfhydryl, NAC can stimulate GSH synthesis, enhancing glutathione-S-transferase activity by acting directly on reactive oxidant radicals.21 In vivo, NAC can increase intracellular GSH levels in erythrocytes and in liver and lung cells, and it can replenish GSH stores following experimental depletion.22,23

NAC is best known as an antidote for acetaminophen (Tylenol) overdose. When administered accordingly, NAC acts as a precursor of intracellular GSH.24 Taken in large doses, acetaminophen depletes glutathione levels and inhibits cytosolic glutathione transferase activity. However, acute NAC administration (~1 hour) afterward prevents these effects.25

Similarly, NAC corrects the reduction in glutathione concentration, resulting in a significant preservation of membrane fluidity, catalase activity and mitochondrial superoxide dismutase activity in biliary obstructed rats. These effects of NAC suggest it may be a useful agent in preserving liver function in patients with biliary obstruction.26

An important observation is that NAC appears to support the synthesis of GSH under conditions where the demand for GSH is increased. However, in the absence of increased stress on the glutathione pools, NAC may have no effect on plasma GSH. This was demonstrated in healthy volunteers who consumed 30mg/kg of NAC in the absence of a hepatic challenge (ie, drug consumption), whereby no increase in total cysteine and free and total glutathione were observed in the plasma. In contrast, following 2g of acetaminophen, co-ingested with 2g NAC, test participants accordingly showed an increase in cysteine and GSH concentrations.27 With this in mind, alcohol has been shown to reduce GSH concentrations, thus increasing the GSH demand.28,29

Alpha-Lipoic Acid (ALA)
Studies using animal models have shown ALA to be a potent deterrent of hepatic injury when examining insults such as alcohol poisoning, carbon tetrachloride poisoning and arsenic exposure.30 However, clinical models have been less compelling. For example, an unblinded trial performed on 20 patients with liver cirrhosis treated with 30mg daily for three days, failed to demonstrate any change in serum pyruvate or lactate levels.31

In a double-blinded trial examining the same population, results showed that ALA did not influence the course of the disease. In this same trial, serum aspartate transaminase and alpha-glutamyl transpeptidase were only improved in the control and treated patients (300mg ALA/day for six months) following ethanol abstinence.32

ALA is a potent deterrent of hepatic injury when examining insults such as alcohol, carbon tetrachloride and arsenic poisoning
Furthermore, acute drinking experiments administering ALA as a pretreatment (90mg/day for seven days) before alcohol had no influence on the blood concentration of alcohol, or acetaldehyde, for a period of six hours, though blood levels of lactate, pyruvate, and alpha-ketoglutarate were lower than those seen in the control group without ALA. 33 However, ALA has been shown to be effective in the treatment of wild mushroom poisoning, which is often fatal.

Zulik et al. reported that the injection of ALA at 200mg/daily intravenously was effective in decreasing transaminase levels and hepatomegaly (liver enlargement or swelling) after a week of treatment.

Equally important was the observation that the mortality rate was decreased and all patients recovered normal hepatic and renal function following treatment.34 A similar study administering 300mg/daily of ALA given in mushroom poisoning as soon as the serum transaminase levels were raised also restored hepatic and renal function in poisoned patients.35

ALA also appears to be protective against radiation exposure. In a report following the Chernobyl nuclear accident, children living in contaminated areas were given either 400mg/day ALA or the same dose combined with 200mg/day vitamin E (alpha-tocopherol) for four weeks. Correspondingly, spontaneous leukocyte returned to normal levels following one month of both treatments. In addition, only the ALA group resulted in a significant decrease in the erythrocyte content of glutathione as well as the normalization of kidney and liver functions.36

Picrorhiza kurroa
Picrorhiza kurroa is used in Ayurvedic medicine to treat liver and bronchial problems. Like silymarin, picrorhiza is poorly soluble in water and usually administered as an extract.

Scientifically, picrorhiza has been shown to protect liver cells from a wide variety of insults including poisoning, carbon tetrachloride, ethanol, and acetaminophen, in both in vitro and in vivo experiments.37,38,39,40,41 When compared with silymarin, the hepatoprotective effect was found to be similar, or in some cases, superior to the effect of silymarin.38,42,43,44,45,46

Picrorhiza has been shown to protect liver cells from poisoning, carbon tetrachloride, ethanol and acetaminophen
Picrorhiza may also be of value in the treatment of viral hepatitis. In one study of 32 patients diagnosed with acute viral hepatitis, 15 treated patients receiving picrorhiza root powder (375mg three times/day for two weeks) demonstrated significantly lower liver enzymes (AST and ALT) and bilirubin following treatment. 47

Several mechanisms of action have been preposed for picrorhiza?s mechanism of action. These include antioxidant activity in vitro, possibly contributing to the hepatoprotective effect by reducing lipid peroxidation and free radical damage and the ability to act in similar fashion to that of superoxidedismutase (SOG) and xanthine oxidase inhibitors.48 SOG is an enzyme that catalyzes the conversion of superoxide into hydrogen peroxide and oxygen. Oxygen free radicals are normally removed in the body by SOG enzymes. In humans, xanthine oxidase is normally found in the liver during severe liver damage and released into the blood.

In rat models infected with malaria, several enzymes associated with glutathione function were also restored, including glutathione transferase, glutathione reductase and glutathione peroxidase.49 Generation of lipid peroxides in African desert rats infected with Plasmodium berghei was significantly reduced by picrorhiza at the oral dose of 6mg/kg for two weeks, revealing that picrorhiza also possesses antilipid peroxidative effects.50

Like silymarin, picrorhiza may also influence liver regeneration via the stimulation of nucleic acid and protein synthesis. This was demonstrated in rat livers following the oral administration of picrorhiza.51 Another factor in the hepatoprotection of picrorhiza may be its anti-inflammatory effects. Picrorhiza extracts were found to have an inhibitory effect on such pro-inflammatory cells as neutrophils, macrophages and mast cells.52

Picrorhiza also contains apocynin. Apocynin exhibits powerful anti-inflammatory effects. These include inhibition of neutrophil oxidative burst in vitro without affecting beneficial activities such as chemotaxis, phagocytosis, and intracellular killing of bacteria.53,54,55,56 In in vivo animal models, apocynin inhibits lipopolysaccharide-induced emphysema in hamsters.56 Several hepatotoxins, including paracetamol (acetaminophen) and ethynylestradiol, cause the liver to reduce its production of bile. Bile has an important physiologic function because it is a digestive juice secreted by the liver and stored in the gallbladder, aiding in the digestion of fats. Picrorhiza has been shown to reverse acetaminophen and ethynylestradiol-induced bile suppression by maintaining both bile volume and flow.

Concluding remarks
The use of dietary supplements to support liver health appears to be well established. However, perhaps a distinguishing difference for ?support? is the concept of prophylaxis vs treatment. The weight of research suggests that the ingredients discussed in this article support supplementation as a treatment for when the liver is stressed or insulted due to toxicities imposed on the body via the environment and disease.

An interesting line of inquiry that should stem from these findings is the co-usage of the ingredients discussed with newer pharmaceutical agents that heavily stress the liver — such as statin medications.57 Nonetheless, when taken in the order of presentation, several candidate supplements may provide strong liver support for many insulting liver exposures.

Conrad Earnest, PhD, is director of the Center for Human Performance and Nutrition Research at The Cooper Institute Centers for Integrated Health Research in Texas. Respond: [email protected]

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