~Liver Degenerative Disease, Continued

How the Liver Detoxifies

The liver has three main detoxification pathways:

1. Filtering the blood to remove large toxins.

2. Enzymatically breaking down unwanted chemicals. This usually occurs in two steps, with Phase I modifying the chemicals to make them an easier target for the Phase II enzyme systems.

3. Synthesizing and secreting bile for excretion of fat-soluble toxins and cholesterol.

Filtering the blood is an essential detoxifying function of the liver. As noted earlier, our total blood supply passes through the liver several times a day and at any given time, about a pint of blood is in the liver undergoing detoxification. Blood detoxification is critical because the blood is loaded with bacteria, endotoxins, antigen-antibody complexes, and other toxic substances from the intestines. A healthy liver clears almost 100% of bacteria and toxins from the blood before the blood enters the general circulation.

The second essential detoxifying role of the liver involves a two-step enzymatic process for the neutralization of unwanted chemical compounds, such as drugs, pesticides, and enterotoxins from the intestines. Even normal body compounds such as hormones are eliminated in this way. Phase I enzymes directly neutralize some of these chemicals, but many others are converted to intermediate forms that are then processed by Phase II enzymes. These intermediate forms are often much more chemically active and therefore more toxic than the original substances. Therefore, if the Phase II detoxification system is not working properly, the intermediates linger and cause damage.

Phase I detoxification involves a group of 50-100 enzymes that has been named the cytochrome P450 system. These enzymes play a central role in the detoxification of both exogenous (beginning outside the body, such as drugs and pesticides) and endogenous (coming from inside the body, such as hormones) compounds and in the synthesis of steroid hormones and bile acids.

A side effect of this metabolic activity is the production of free radicals that are highly reactive molecules that will bind to cellular components and cause damage. The most important antioxidant for neutralizing these free radicals is glutathione, which is needed for Phase I and Phase II detoxification. When exposure to high levels of toxin produces so many free radicals from Phase I detoxification that glutathione is depleted, Phase II processes that are dependent on glutathione cease. This causes an imbalance between Phase I and Phase II activity, causing severe toxic reactions as a result of the build-up of toxic intermediate forms.

Phase II detoxification involves conjugation, meaning a protective compound becomes bound to a toxin. Besides glutathione conjugation, the other pathways are amino acid conjugation, methylation, sulfation, sulfoxidation, acetylation, and glucuronidation. These enzyme systems need nutrients and metabolic energy to function. As noted earlier, if liver cells do not function properly, Phase II detoxification slows down and increases the toxic load of toxic intermediates.

The third essential detoxifying role of the liver is synthesis and secretion of bile. The liver manufactures approximately a quart of bile every day. Bile serves as a carrier to effectively eliminate toxic substances from the body. In addition, bile emulsifies fats and fat-soluble vitamins in the intestine, improving their absorption. When the excretion of bile is inhibited (cholestasis), toxins stay in the liver longer and subject the liver to damage.

Free-Radical Damage and Lipid Peroxidation

Oxidative damage from the production of free radicals has far-reaching consequences in the body. Lipid peroxidation is a term that describes fats that have been chemically damaged by oxygen free radicals. Cell membranes consist mainly of layers of phospholipids. As free radicals attack the cell membrane, injury and eventual death to the cell occur due to DNA strand breakage. DNA is the cellular blueprint that is required for replication. Oxidative stress also affects circulating lipids in the body including cholesterol, 80% of which is produced in the liver. Peroxidized cholesterol has been shown to damage arteries, leading to atherosclerosis, and a growing body of evidence supports a role for lipid peroxidation in the continued development of liver damage.

While cell damage in the human liver is likely multifactorial, free radicals have been implicated in a variety of liver diseases, particularly in the presence of iron overload, ethanol consumption, and ischemia/reperfusion injury, either initiating or perpetuating liver damage. Additionally, free radical-initiated lipid peroxidation appears to play a role in hepatic fibrogenesis (Britton et al. 1994). The role of free radicals is significant in toxic liver injury that is often induced by drugs and chemicals. Damage is first caused by the toxin itself and then is continued when the toxin is metabolized by the liver (Feher et al. 1992).

TREATMENT OF DEGENERATIVE LIVER CONDITIONS

* Conventional Medical Therapy
* Natural Therapies
* Supplements that Maintain Metabolic Health
* Antioxidants that Reduce Free-Radical Damage
* Protecting and Improving Liver Function

Conventional Medical Therapy

Unfortunately, liver damage caused by degenerative conditions is irreversible. There are no commonly accepted, effective, conventional drug therapy regimes to prevent or reverse liver damage. Treatment primarily consists of identifying the underlying causes of disease, determining possible steps to slow or stop progression of degeneration, and managing symptoms. One causal factor is alcohol: stopping the intake of alcohol will help stop progression. Ending the use of hepatoxic drugs and removing sources of environmental toxins will also stop progression. The possible presence of metabolic diseases (hemochromatosis, Wilson's disease) should be investigated. Identifying the presence of hepatitis viruses is essential. Because obesity plays an important role in fatty liver, attention to weight control is essential.

Conventional drug therapies can include:
  • Colchicine, a generic drug used to treat gout, also inhibits collagen (a protein in the body the makes up scar tissue) and has produced some improvement in liver function and patient survival (Nidus 1999).
  • Corticosteroids that reduce inflammation have been helpful in improving liver function and symptoms, but these drugs have potentially serious side effects (Glanze 1996). (If taking a corticosteroid, measures must be taken to monitor adverse side effects such as edema, hypertension, diabetes mellitus, osteoporosis, and ulcers.)
  • Malotilate (a drug developed in Japan) prevents damage to liver cells (and cirrhosis) induced in laboratory animals. It has been shown by several researchers to prevent induced liver damage, the accumulation of collagen, and morphologic changes (such as accumulation of inflammatory cells and fibrosis and to reduce ethanol induced lesions) (Takase et al. 1989; Mirossay et al. 1996; Ryhanen et al. 1996).
  • Alpha interferon (Intron A) and ribavirin (Rebetol and Virazole) are antiviral drugs used in treating the hepatitis viruses. These drugs are a mainstay for some persons (NIDA 2002). However, some patients are not responsive; experience relapse after the antiviral drugs are discontinued; or have great difficulty handling the side effects (Strickland 2002). Newer alpha interferon drugs are pegylated, meaning they contain polyethylene glycol combined with interferon. At this writing, only one pegylated drug has been approved by the FDA. PEG-Intron was approved by the FDA in January 2001 for once-weekly therapy for the hepatitis C virus. Another drug, PEGASYS, is undergoing Phase III clinical trials, awaiting approval by the FDA.
  • Gene therapy as a treatment option is the subject of research, but even if research indicates that gene therapy appears feasible, human trials are years away.
Itching is a very troublesome symptom for patients with liver disease. It is also a very difficult symptom to manage for physicians. The reason why patients with liver disease itch is not understood. One thought is that certain substances accumulate in the blood as a result of liver disease and cause itching. The nature of these substances is under investigation, but some evidence suggests that normal substances found in blood plasma (e.g., endogenous opioids known as enkaphalins) for some unknown reason cause itching in liver disease patients. Itching/scratching studies have also shown that some patients manifest scratching in a 24-hour rhythm (circadian), suggesting that neurotransmitters in the brain may cause itching (Bergasa 2002). At this time, little treatment is available for itching secondary to liver disease:
  • Cholestyramine (taken with food) and Naltrexone can help relieve itching (Nidus 1999). (High doses of Naltrexone are toxic for the liver, but low doses appear to be safe.)
  • Phototherapy (light therapy) has been helpful in reducing itching (Nidus 1999).


Natural Therapies

Scientific literature reports the results of research using natural or alternative treatments for liver conditions. Note that the vast majority of natural or alternative treatments act by having an antioxidant effect. As with almost all disease processes, research has demonstrated that good antioxidant levels are necessary for optimum health and to protect us from the physical assaults of trauma and disease. Some of the therapies listed in the following section also act by having an effect on the immune system (an immune-modulating effect). Other therapies have anti-inflammatory benefits. Additionally, some agents act by having both antioxidant mechanisms and immune modulating mechanisms.

For the liver to continue to perform essential functions, even when damaged, a healthy intake of vitamins, minerals, and essential trace elements from dietary sources such as fruits and vegetables is important. However, few people can consistently include enough fruits and vegetables in their daily diets to protect them from degenerative conditions, especially those related to age-related diseases; toxic agents; carcinogens; inflammatory agents; free-radical damage; and immune suppression. As an adjunct to maintaining a healthy diet, supplements can:

1. Maintain healthy metabolic functioning

2. Neutralize free-radical damage

3. Increase levels of glutathione, the liver's natural antioxidant

4. Detoxify the liver

Supplements that Maintain Metabolic Health

Vitamin B complex. The vitamin B complex is a group of vitamins (B1, thiamine; B2, riboflavin; B3, niacin; B5, pantothenic acid; B6, pyridoxine; and B12, cyanocobalamin) that differ from each other in structure and the effect they have on the human body. The B vitamins play a vital role in numerous essential activities including enzyme activities (thiamine, riboflavin, niacin, pantothenic acid, pyridoxine). These enzyme activities also have many roles and are involved in the metabolism of carbohydrates and fats; functioning of the nervous and digestive systems; and production of red blood cells. The B vitamins have a synergistic effect with each other (AMA 1989). They are found in large quantities in the human liver as well as in many foods and yeast.

Folic acid. Folic acid is an important member of the B-complex family, important for reducing harmful levels of homocysteine, a sulfur-containing amino acid, known to be a major culprit in heart disease. The liver uses folic acid to facilitate healthy methylation patterns that are essential components of enzymatic detoxification. Decreased folate (folic acid) is also associated with increased levels of lipoperoxidases, that is, an indicator of increased oxidative stress. Therefore, folic acid is potentially beneficial if there is ongoing oxidative damage (Chern et al. 2001).

Choline. Another of the B complex vitamins is choline, essential for the use of fats in the body. It comprises a large part of acetylcholine (a nerve signal carrier). Choline also stops fats from being deposited in the liver and helps move fats into the cells. Deficiency of choline can lead to degenerative diseases such as cirrhosis with associated conditions such as bleeding, kidney damage, hypertension (high blood pressure), cholesterolemia (high blood levels of cholesterol), atherosclerosis (cholesterol deposits in blood vessels), and arteriosclerosis (hardening of the arteries) (Glanze 1996).

Acetyl-L-carnitine. Acetyl-L-carnitine has been shown to convert some hepatic parameters to more youthful levels. Acetyl-L-carnitine is the biologically active form of the amino acid L-carnitine that has been shown to protect cells throughout the body from age-related degeneration. By facilitating the youthful transport of fatty acids into the cell mitochondria, acetyl-L-carnitine facilitates conversion of dietary fats to energy and muscle. Acetyl-L-carnitine has also been shown to regenerate nerves (Fernandez et al. 1997), to provide protection against glutamate and ammonia induced toxicity to the brain (Rao et al. 1999), and to reverse the effects of heart aging in animals (Paradies et al. 1999).

Antioxidants that Reduce Free-Radical Damage

Vitamin C. Vitamin C is a potent antioxidant that is found naturally in many fruits and vegetables. According to Garg et al. (2000), vitamin C has protective effects against liver oxidative damage, particularly when used in combination with vitamin E. Researchers have found inadequate levels of vitamin C in patients with degenerative diseases. Garg et al. (2000) found that supplementation in rats lowered plasma and liver lipid peroxidation, normalized plasma vitamin C levels, and raised vitamin E above normal levels.

Vitamin E. Vitamin E protects the lipid membrane from oxidative damage. Adequate levels of vitamin E also protect cholesterol from oxidative damage. Oxidized cholesterol damages arteries and contributes to atherosclerosis (Mydlik et al. 2002). Hepatocytes incorporate vitamin E into lipoproteins, which then transport it to various tissues in the body.

Coenzyme Q10 (CoQ10). CoQ10 is an antioxidant that is protective for a liver that has been damaged by ischemia (reduced blood flow) (Genova et al. 1999). CoQ10 is also an important component of healthy metabolism. It protects the mitochondria and cell membrane from oxidative damage and helps generate ATP, the energy source for cells. CoQ10 is absorbed by the lymphatic system and distributed throughout the body. Japanese researchers studied the effects of the toxic drug hydrazine on liver cells. Hydrazine caused remarkable increases in intracellular levels of reactive oxygen species in hepatocytes, which were suppressed by CoQ10 (Teranishi et al. 1999).

N-acetyl-cysteine (NAC). N-acetyl-cysteine is an amino acid that acts as an antioxidant or free-radical scavenger. Most scientific articles related to liver protection with NAC emphasize this effect. NAC is frequently used in medical settings to treat liver toxicity associated with ingesting Tylenol (also poisonous mushrooms) (Hazai et al. 2001; Attri et al. 2001).

Alpha-lipoic acid (ALA). Alpha-lipoic acid is an antioxidant that has been shown to decrease the amount of hepatic fibrosis associated with liver injury. Both of these mechanisms suggest it has promise for cirrhosis. Because alpha-lipoic acid is fat soluble, it can penetrate the cell membrane to exert therapeutic action. It has been shown to effectively scavenge harmful free radicals, chelate toxic heavy metals, and help to prevent mutated gene expression (Biewenga et al. 1997). Another of its most beneficial functions is to enhance the effects of other essential antioxidants including glutathione, which is vital to the health of the liver (Lykkesfeld 1998; Khanna et al. 1999).

Selenium. Selenium is a trace element that acts by several mechanisms, including detoxifying liver enzymes, exerting anti-inflammatory effects, and providing antioxidant defense. The presence of selenium helps induce and maintain the glutathione antioxidant system (Sakaguchi 2000).

Zinc. Zinc is an essential dietary nutrient and is used in numerous drugs and preparations that are protective. Zinc helps remove copper from the body and is used as an adjuvant treatment in Wilson's disease (Brewer et al. 1999).

Protecting and Improving Liver Function

S-adenosylmethionine (SAMe). SAMe is a methylation agent (a methyl group donor) and is necessary for the synthesis of glutathione. Medical studies have shown that SAMe has beneficial antioxidant effects on the liver and other tissues, particularly in protecting and restoring liver cell function destroyed by the hepatitis C virus. SAMe decreases the production of liver collagen, which leads to the formation of fibrous tissue (Deulofeu et al. 2000). SAMe is found naturally in every cell of the body. It is synthesized from a combination of the amino acid L-methionine, folic acid, vitamin B12, and trimethylglycine, provided all these ingredients are present and performing (Anon. 2002).

Phosphatidylcholine (PC). Phosphatidylcholine is a type of fat that is part of cell membranes. PC is one of the most important substances for liver protection and health and is a primary constituent of cell membranes. PC acts by several mechanisms: exerting potent antioxidant effects; inhibiting the tendency of stellate cells to progress to cirrhosis; decreasing apoptotic death of liver cells and thereby prolonging the life of liver cells; stabilizing the cell membrane, thus improving the integrity and function of the liver cell; and exerting an antifibrotic effect related to the breakdown of collagen (not only slowing the progression of fibrosis, but also encouraging regression of existing fibrosis) (Ma 1996; Lieber 1999; Pniachik 1999; Wolf 2001). A special form of PC called polyenylphosphatidylcholine has been shown to prevent the early changes in the damaged liver from occurring before the actual development of cirrhosis (Navender 1997).

Silymarin. Silymarin, (also known as milk thistle or Silybum marinum) is a member of the aster family (Asteraceae). The active extract of milk thistle is silymarin (Bosisio et al. 1992), a mixture of flavolignans, including silydianin, silychristine, and silybin, with silybin being the most biologically active. Silymarin has proven to be one of the most potent liver-protecting substances known. Its main routes of protection appear to be the prevention of free-radical damage, stabilization of plasma membranes, and stimulation of new liver cell production. It has also been shown to inhibit lipid peroxidation and to prevent glutathione depletion induced by alcohol and other liver toxins, even increasing total glutathione levels in the liver by 35% over controls (Valenzuela et al. 1989). Early studies show that silymarin has the ability to stimulate protein synthesis, resulting in production of new liver cells to replace older, damaged ones (Sonnenbichler et al. 1986a; 1986b). Studies also demonstrate the benefits of silymarin for protection from numerous toxic chemicals.

Branched-chain amino acids. Branched-chain amino acids (leucine, isoleucine, and valine) are considered to be essential amino acids because humans cannot survive unless these amino acids are present in the diet. Branched chain amino acids (BCAAs) are needed for the maintenance of muscle tissue and appear to preserve muscle stores of glycogen (stored form of carbohydrates that can be converted into energy). Dietary sources of BCAAs are dairy products and red meat. Whey protein and egg protein supplements are other sources. Most diets provide the daily requirement of BCAAs for healthy people. However, in cases of physical stress, we have increased energy requirements, in particular persons with cirrhosis. Studies on alcoholic cirrhosis patients have shown benefits from supplementing valine, leucine, and isoleucine. These branched-chain amino acids can enhance protein synthesis in liver and muscle cells, help restore liver function, and prevent chronic encephalopathy (Shimazu 1990; Chalasani et al. 1996) In studies, BCAAs have also been shown to have therapeutic value in adults with cirrhosis of the liver. According to the researchers, BCAAs seem to be the preferred substrate to meet this requirement (Kato et al. 1998).

SUMMARY

If you already have a degenerative liver condition, or have symptoms of liver disease, consult a qualified physician who is experienced in treating liver disease and who will coordinate your treatment. Supplementation with antioxidants, branched-chain amino acids, and all of the B complex of vitamins except B3 (niacin) has been shown to have protective qualities and to be beneficial for the liver. The following are important in preventing liver disease and for providing beneficial supportive effects.

1. The B vitamins are essential for healthy metabolic functioning. Working individually and synergistically, they facilitate energy release and the manufacture of new cells.
  • B1 (thiamine), 500 mg
  • B2 (riboflavin), 75 mg
  • B5 (pantothenic acid), 1500 mg
  • B6 (pyridoxine), 200 mg
  • B12 (cobalamin), sublingual methylcobalamin is recommended for better absorption, one 5-mg lozenge 1-5 times daily
  • Folic acid, 800 mcg daily
  • Vitamin B3 (niacin) should be avoided by people with liver conditions as it disrupts healthy methylation patterns.
2. Choline helps reduce the amount of fat deposited in the liver, 1500 mg daily.

3. Acetyl-L-carnitine will help to maintain mitochondrial health, take 2 daily doses of 1000 mg.

4. Antioxidants will protect the liver from the damaging effects of free radicals produced from environmental toxins.
  • Take at least 2500 mg of vitamin C daily.
  • Vitamin E (400 IU of D-alpha tocopheryl succinate and 200 mg of gamma tocopherol daily provide broad-spectrum antioxidant protection).
  • CoQ10 protects the mitochondria from oxidative damage and provides cellular energy, 100-300 mg daily.
  • N-acetyl-cysteine (NAC) enhances the production of glutathione and has protective benefits for the liver from toxins. Take 600 mg daily.
  • Alpha-lipoic acid can dramatically increase glutathione levels inside of cells. Suggested dose is 250 mg 2-3 times a day.
  • The trace mineral selenium has shown antioxidant protection in the liver. Zinc is often deficient in the cirrhotic liver and acts as a chelator in removing copper from the system. Take selenium, 200 mcg daily, and zinc, 30-85 mg daily.
5. Several supplements can benefit a damaged or diseased liver:
  • S-adenosylmethionine (SAMe) is needed to synthesize glutathione and has restored liver function from damage due to hepatitis C. The suggested dose of SAMe is 400 mg 3 times daily. Do not take SAMe on an empty stomach.
  • Polyenylphosphatidylcholine (PPC) has been shown to prevent the development of fibrosis and cirrhosis and to prevent lipid peroxidation and associated liver damage from alcohol consumption. PPC is sold as a drug in Europe. A product called HepatoPro (formerly GastroPro) is one of the few American dietary supplements to provide pharmaceutical-grade polyenylphosphatidylcholine. Take two to three 900-mg capsules daily.
  • Silymarin extract from milk thistle can raise glutathione levels and has shown multi-faceted protective benefits to the liver. The most active flavonoid in silymarin is silibinin. A product called Silibinin Plus is formulated to provide the same silibinin extract used in European prescription drugs. One 325-mg capsule taken twice daily is recommended for healthy people. Patients with liver disease may take up to 6 capsules daily.
  • Branched-chain amino acids can enhance protein synthesis in the liver and are particularly beneficial in alcoholic cirrhosis. The suggested dose is 2-4 capsules daily between meals with fruit juice or before eating. Each capsule should contain 300 mg of leucine, 150 mg of isoleucine, and 150 mg of valine.
More information on conventional therapies is available by contacting the American Liver Foundation, (800) 223-0179.


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