Reprinted with permission of Life Extension®.
- Liver Function
- Free-Radical Damage And Lipid Peroxidation
When compared to other health conditions, it is striking how little attention is given to diseases of the liver, particularly considering the rising level of concern about health and health-related environmental issues. Hepatoprotection (or protection of the liver) is a subject that should be of intense interest because the liver plays a critical role in all aspects of metabolism and overall health.
This protocol will present intriguing information about the role of the liver and explain why a well-functioning liver is essential for overall health. Also identified will be environmental hazards that constantly challenge the detoxification capacity of the liver. Research on the effects of alcohol on the liver will be discussed. Additionally, you will learn what you can do to support and optimize the function of your liver and thus optimize your future health and quality of life.
Some beneficial herbs will also be described. In Europe and Asia, herbal liver tonics have been in common use for decades--perhaps even for centuries. The effectiveness of the herbs used in these remedies has been validated during the past several decades through research and clinical studies. These herbs generally contain antioxidants; membrane-stabilizing and bile-enhancing compounds; or substances that prevent depletion of sulfhydryl compounds, such as glutathione.WHAT DOES THE LIVER DO?
The liver is located on the right side of the body in the upper abdomen. In the human, it is the second largest organ of the body, weighing about 4 lbs (skin is the largest organ). Even while being exposed to tremendous potential for damage, the liver performs a multitude of essential functions: metabolizing, detoxifying, and regenerating. It does an extraordinary job of keeping us alive and healthy by metabolizing the food we eat, that is, breaking it down into useful parts, and by having detoxifying abilities that protect us from the damaging effects of numerous toxic compounds that we are exposed to on a daily basis. Several times each day, our entire blood supply passes through the liver. At any given time, about a pint of blood is in the liver (or 10% of the total blood volume of an adult) (NIDDK 2000). In addition, the liver has impressive restorative capabilities and is the only organ in the body that is capable of regenerating itself when part of it has been damaged.
The metabolizing functions of the liver are numerous. The liver is intricately involved in carbohydrate, fat, and protein metabolism; in the storage of vitamins and minerals; and in many essential physiological processes. The liver is also involved in several regulatory mechanisms that control blood sugar levels and hormone levels. It synthesizes proteins (such as plasma albumin, fibrinogen, and most globulins) and lipids and lipoproteins (phospholipids, cholesterol), as well as bile acids that are excreted in the detoxification process (NIDDK 2000).
Other important functions of the liver include production of prothrombin and fibrinogen (two blood-clotting factors) and heparin (a mucopolysaccharide sulfuric acid ester that helps prevent blood from clotting within the circulatory system). The liver also processes glucose into glycogen and stores it until the muscles need energy; some glucose is also converted into fat and stored. The released glycogen becomes glucose in the bloodstream.
Additionally, the liver produces and secretes bile (stored in the gallbladder), that is needed to break down and digest fatty acids, and produces blood protein and hundreds of enzymes needed for digestion and other bodily functions. As the liver breaks down proteins, it produces urea, which it synthesizes from carbon dioxide and ammonia. (Urea is the primary solid component of urine, and it is eventually excreted by the kidneys.) Essential trace elements such as iron and copper as well as vitamins A, D, and B12 are also stored in the liver.
The detoxifying function is an essential part of human body metabolism, with the liver playing a key role in the process. Toxic chemicals, of both internal and external origin, constantly bombard the liver. Even our normal everyday metabolic processes produce a wide range of toxins that are neutralized in the liver.
The regenerating capacity of the liver is one of the most intriguing survival mechanisms of the body. The liver is an incredibly resilient organ. Up to 75% of its cells can be surgically removed or destroyed by disease before it ceases to function (AMA 1989). As with some other organs, the liver has been designed with an excess of tissue to protect it from damage or loss of function. The healthy parts of the liver have an amazing capacity to regenerate new, healthy liver tissue to replace damaged liver tissue. We are very fortunate that the liver has a regeneration capacity because our health depends on a well-functioning liver.CONDITIONS LEADING TO LIVER DAMAGE
* Wilson's Disease
* Autoimmune Hepatitis
* Hepatitis B
* Hepatitis C
* Steatosis, Steatohepatitis, and Cirrhosis
* Toxic Damage to the Liver
The symptoms that are indicative of reduced liver function or possible liver damage include general malaise; fatigue; digestive disturbances such as constipation; allergies and chemical sensitivities; weight loss; jaundice; edema; and mental confusion. Generalized pruritus (itching), nausea, and vomiting can also result from impaired hepatofunction. The causes of liver damage are numerous and may include congenital defects (malformed or absent bile ducts); obstructed bile ducts (cholestasis); autoimmune disorders; metabolic disorders (hemochromatosis, Wilson's disease); tumors; toxins (drugs, overdoses, poisons); alcohol-related conditions (cirrhosis); bacterial and parasitic infections; and viral infections (hepatitis B and C). This section discusses several chronic disorders and diseases that can lead to degenerative liver damage without proper diagnosis and treatment.Cholestasis.
Cholestasis is interruption or stagnation of the bile flow in any part of the biliary system, beginning with the liver. Cholestasis has several causes, including obstruction of the bile ducts by the presence of gallstones or a tumor, drug and alcohol use, hepatitis, and existing liver disease (Glanze 1996). In the United States, an important cause of cholestasis and impaired liver function is the consumption of alcohol. Other common causes of cholestasis are viral hepatitis and the side effects of various drugs, particularly steroidal hormones (including estrogen and oral contraceptives).
Cholestasis can cause alterations of liver function tests, indicating cellular damage. In the initial stages of liver dysfunction, standard tests (serum bilirubin, alkaline phosphatase, SGOT, LDH, GGTP, etc.) may not be sensitive enough to be of value for complete, early diagnosis. However, the measurement of serum bile acids is a safe, sensitive test to determine the functional capacity of the liver. Treatment for cholestasis includes surgery so that there will be unobstructed bile flow from the liver. Drug-induced cholestasis will generally disappear if the causative drug is discontinued. There is no specific treatment for cholestasis caused by hepatitis. However, bile flow will improve slowly if inflammation of the liver can be resolved.Wilson's Disease.
Wilson's disease is an inherited disorder characterized by the liver's inability to metabolize copper, resulting in the accumulation of excessive amounts of copper in the brain, liver, kidney, cornea, and other tissues. The resulting copper accumulation and toxicity result in liver disease and cause brain damage in some patients. Although deposits of copper begin at birth, it may be some time until the symptoms of liver disease become evident. Patients, generally between the ages of 10-40, present symptoms of liver disease; a movement disorder associated with neurological disease; behavioral abnormalities; or often a combination of these. Blood testing will reveal elevated liver enzymes. Symptoms of hepatitis and cirrhosis may be evident. Secondary injury from the accumulation of copper in the body may include kidney damage, neurological disorders, hemolytic anemia, and osteoporosis.
Copper also accumulates in other body organs, particularly the brain, and may result in difficulty with speech, trembling, writing problems, unsteady gait, depression, suicidal impulses, and loss of mental functions. The other body organs may also be damaged by copper overload. Copper can accumulate in the cornea of the eye and cause a characteristic brown pigmentation called Kayser-Fleischer rings. Hemolytic anemia, a low blood count related to damage of red blood cells, may occur in patients with Wilson's disease. There may also be injury to the kidneys from copper overload. Finally, severe bone disease from osteoporosis can occur in patients with Wilson's disease.
If Wilson's disease is left untreated, increasing damage to body organs will occur, especially in the liver and brain. D-penicillamine is a copper chelating agent that is administered to remove excess copper and prevent further accumulations. Trientine may also be used as a copper chelating agent. Both drugs are administered with vitamin B6 (see the Heavy Metal Toxicity protocol for additional information on chelation). Foods high in copper content such as shellfish, nuts, chocolate, liver, and mushrooms must be avoided.
Because Wilson's disease can be effectively treated, it is extremely important for physicians to learn to recognize and diagnose the disease. Treatment options have evolved rapidly in the last few years, with zinc now being an important choice in most situations (Brewer et al. 1999). Brewer et al. (1999) consider zinc to be so important in the treatment of Wilson's disease that they refer to it as being "the drug of choice."
Wilson's disease requires management by a physician. Self-treating this condition with zinc is not recommended.Autoimmune Hepatitis.
Autoimmune hepatitis is associated with an increase in circulating autoantibodies and gammaglobulin resulting in progressive inflammation of the liver. The symptoms of Type-I autoimmune hepatitis (the most common) are characterized by the presence of antinuclear antibodies and a resemblance to symptoms of systemic lupus erythematosus. The disease occurs most commonly in females during adolescence or early adulthood. Other autoimmune disorders may be present with autoimmune hepatitis including thyroiditis, ulcerative colitis, vitiligo (loss of skin pigmentation), and Sjogren's syndrome (characterized by dry mouth and eyes).
Fatigue, abdominal discomfort, aching joints, itching, jaundice, enlarged liver, and spider angiomas (blood vessels) on the skin are the most common symptoms. More severe complications of liver disease may occur as the disease progresses.
Up to 80% of patients have long-term survival with appropriate treatment. Prednisone and azathioprine are usually administered to treat immunosuppression. The goal of treatment is to control rather than cure the disease.Hepatitis B.
In the United States and Europe, approximately 1.25 million people are chronically infected with the hepatitis B virus (Malik et al. 2000). About 5-10% of those with acute hepatitis B will develop chronic infection. The remainder will recover and develop antibodies to the virus that make them immune from further viral activity (Lammert et al. 2000; Mayerat et al. 1999). At least 1 million chronically infected individuals die each year of complications due to HBV-related diseases, especially liver cancer and cirrhosis. In the entire world, about 5% of the population or 350 million people have chronic hepatitis B (Gumina et al. 2001).
Hepatitis B causes inflammation of the liver resulting from infection with a DNA-type virus. The infection is passed via blood products, as in transfusions or in the sharing of contaminated needles. It may also be acquired by exposure to body fluids in addition to blood, during sexual intercourse, and in transmission from mother to fetus. About 5-10% of volunteer blood donors show evidence of having prior hepatitis B--meaning that they once did have hepatitis B and may or may not still be infectious with the viral agent.
The incidence of hepatitis B is increased in dialysis patients, IV drug users, persons with AIDS, transplant recipients, and patients frequently receiving blood transfusions such as those with leukemia or lymphoma. When acute hepatitis occurs, symptoms include weakness, nausea, vomiting, body aches (myalgias), diarrhea, fever, joint pains (arthralgias), jaundice (yellow discoloration of the skin and whites of the eyes), loss of appetite, weight loss, loss of interest in tobacco products, and sometimes an itching skin rash. The average duration of symptoms of acute hepatitis B is 1-3 months. During the final phase of symptoms, the body begins to build immunity against the hepatitis B infection and does become immune 90% of the time (Lammert et al. 2000). In the other 10%, however, a state of persistent infection occurs for more than 6 months. These persons are designated as having chronic hepatitis B. A liver biopsy is done in those patients having chronic hepatitis B and about one-third of these have chronic active hepatitis and two-thirds have chronic persistent hepatitis. Of these two types, the chronic active hepatitis is more aggressive and has a more rapidly progressing course.
Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine (Epivir). A vaccine for hepatitis B now exists and is frequently given to newborns, overseas travelers, and other people at risk to exposure (refer to the Hepatitis B protocol for more information and specific therapies).Hepatitis C.
Hepatitis C can be transmitted by blood and blood product transfusion. Up to 170 million persons are infected worldwide. In the United States, more than 4 million people are infected with HCV. Most liver transplants in the United States are a result of hepatitis C. Hepatitis C has a frightening tendency to result in chronic hepatitis, resulting in cirrhosis (15-20% of those infected) or hepatocellular carcinoma (primary liver cancer) (Ou 2002).
The hepatitis C virus (HCV) is an RNA virus, spherical and enveloped in a lipid (fatty) outer envelope, which can be transmitted by narcotics use, transfusion of blood products, and exposure of medical personnel to infected patients. In some cases, the reason one contracts hepatitis C cannot be determined. The hepatitis C virus inflicts most of its damage by latching onto molecules of iron and generating free-radical damage to liver cells. These free radicals can induce liver inflammation, cirrhosis, and primary liver cancer via oxidative attacks on liver cells.
Successful eradication of the hepatitis C virus from the body often requires that iron levels in the liver and blood be at very low levels. In many cases, high stores of iron in the liver preclude successful therapy against the hepatitis C virus. It is desirable to reduce iron levels in the body before initiating treatment with conventional (interferon and ribavirin) therapy. Despite substantial scientific evidence, few physicians implement iron-depletion therapy when treating hepatitis C. This partially accounts for the high failure rate to eradicate the virus.
In patients with hepatitis C, particularly those who are HIV-positive, a systemic depletion of glutathione is present, especially in the liver. This depletion may be a factor underlying the resistance to interferon therapy. This finding represents a biological basis for taking supplements that boost cellular glutathione levels. Glutathione is a critical factor in protecting liver cells against free-radical damage.
Standard therapy for hepatitis C has consisted of ribavirin combined with interferon. However, a combination therapy of peginterferon alpha-2b and ribavarin is currently the standard of care (refer to the Hepatitis C protocol for more information and specific therapies).Hemochromatosis.
Hemochromatosis is a hereditary disorder in which too much iron is absorbed from the diet resulting in free-radical damage to the liver, heart, and pancreas. It is estimated that over 1 million Americans suffer from the disease. If diagnosed early, hemochromatosis can be controlled by phlebotomy (giving blood) until stored iron levels are reduced. High levels of antioxidants and herbal detoxifiers are usually recommended to neutralize free radicals generated by excess iron. Chelation therapy is an alternative treatment in which a synthetic amino acid is administered intravenously to bind and extract unwanted metals from the body. People with hemochromatosis must avoid iron-fortified foods, cast-iron cookware, and red meat. Symptoms may not appear until middle age, after multiple organ damage has occurred. Due to blood loss from menstruation and pregnancy, the disease is less prevalent in women than men (refer to the Hemochromatosis protocol for more information and specific therapies).Steatosis, Steatohepatitis, and Cirrhosis.
Steatosis (or fatty liver) is a common finding in biopsy of the human liver. Fatty liver is a condition in which fat accumulates within the liver cells (hepatocytes) without causing any specific symptoms. (Fatty liver is defined as either more than 5% of cells containing fat droplets or total lipid exceeding 5% of liver weight.)
Fatty liver is usually a long-standing chronic condition, occurring in association with a wide range of diseases--exposure to poisonous and toxic substances, taking certain drugs, and drug abuse (injecting recreational drugs) (Glanz 1996)--although in clinical practice, the majority of cases are the result of excessive use of alcohol, diabetes, and obesity. Less common are occurrences of acute fatty liver during pregnancy or as a response to the administration of tetracyclines, acetaminophen, prescription drugs, and toxins.
Our understanding of the fatty liver condition has advanced considerably. At one time, fatty liver was believed to be a benign, reversible condition. However, clinical studies now demonstrate that fatty liver, whether from alcoholic or nonalcoholic origin, can lead to inflammation, cell death, and fibrosis (steatohepatitis), perhaps even progression to cirrhosis. Cirrhosis is the irreversible end result of fibrous scarring, a response by the liver to a variety of long-standing inflammatory, toxic, metabolic, and congestive damage processes (refer to the Liver Cirrhosis protocol for more information and specific therapies).
As stated earlier, in the Western world, alcohol is a common cause of fatty liver and is the second most common cause of cirrhosis. However, there are considerable inter-individual differences in the degree of liver damage produced by excessive alcohol intake. There seems to be no correlation between the incidence and severity of fatty liver and either the amount, type, or duration of alcohol abuse. In some individuals, it is unclear why fatty liver, whatever its etiology, never progresses to steatohepatitis and cirrhosis.
Obesity is among the causes for nonalcoholic steatohepatitis (NASH) and is considered to be the most common cause. There is evidence to suggest that liver disease can actually be considered to be a complication of obesity. However, no major prospective longitudinal studies of NASH have been carried out. Generally, it seems that the risk of progression to cirrhosis is low for nonobese individuals, but significant among obese individuals. Unfortunately, there is also no predictable correlation between symptoms (or lack of them), abnormality of liver function tests, and severity of liver tissue damage.
As early as 1985, a study of 50 unselected, obese subjects who were admitted to a hospital for weight reduction found that 10% had normal livers, 48% had fatty livers, 26% had steatohepatitis, 8% had fibrosis, and 8% had cirrhosis (Braillon et al. 1985). Obesity was defined as being 21-130% above ideal body weight.
Interestingly, among patients with fatty liver related to obesity, it has been observed that rapid weight loss caused by dieting and intestinal bypass surgery actually increased the risk for developing steatohepatitis. The resulting increase in the concentration of fatty acids and/or ketones within the liver severely augmented the generation of free radicals (Day et al. 1994).
A study by Yang et al. (1997) indicated that obesity also increases susceptibility to endotoxin-mediated liver injury. Endotoxins are cell wall components produced by intestinal Gram-negative bacteria that are thought to play a role in liver injury induced by alcohol and other hepatotoxins. Under normal conditions, endotoxins are absorbed into the portal venous circulation and detoxified by the liver. Hepatic dysfunction interferes with this clearing mechanism and amplifies the negative activities of endotoxin, such as lipid peroxidation, reduced P-450 function, and impairment of the immune system.
Berson et al. (1998) summarized well insights from research on the mechanisms of steatohepatitis:
Its development requires a double hit, the first producing steatosis, the second a source of oxidative stress capable of initiating significant lipid peroxidation. This concept provides a rationale for both the treatment and prevention of disease progression in steatosis of alcoholic and non-alcoholic causes. Management strategies should ideally be directed at reducing the severity of steatosis and at avoiding and removing the triggers of inflammation and fibrosis. Specific treatment modalities for at-risk individuals might include sensible weight reduction, cessation of exposure to toxins and treatment with antioxidants and inhibitors of peroxisomal
Toxic Damage to the Liver.
It is the external environment that contributes most to the load of toxins that the liver has to detoxify. Today, the burden on the liver is heavier than ever before in history. Additionally, nutritional deficiencies and imbalances from unhealthy eating habits add to the production of toxins, as do alcohol and many prescription drugs, further increasing stress on the liver and requiring a strong detoxification capacity. Surprisingly, even unprocessed organic foods can have naturally occurring toxic components that require an effective detoxification system.
Toxic chemicals are found in the food we eat, in the water we drink, and in the air we breathe, both outdoors and indoors. In a study by the Environmental Protection Agency (EPA), chemicals such as p-xylene, tetrachloroethylene, ethylbenzene, and benzene were documented as "everywhere present" in the air (Wallace et al. 1989). Listed as "often present" were chloroform, carbon tetrachloride, styrene, and p-dichlorobenzene. A customary trip to a gas station or a dry cleaner (as well as smoking) results in elevated levels of inhaled toxins.
The Food and Drug Administration (FDA) has found an alarming level of chlorinated pesticides in food. Dichlorodiphenyldichloroethylene (DDE) was found in 63% or more of 42 food samples, even though the use of dichlorodiphenyltrichloroethane (DDT) and DDE has been banned in the United States since 1972. DDE is a breakdown product of DDT. Unfortunately, carried by the winds, toxic chemicals used anywhere in the world can move easily around the globe. There is enough evidence of a connection between chemical exposure and chronic health problems for us to be aware that herbicides, pesticides, household chemicals, food additives, etc. pose serious health concerns.
So what happens when the liver's detoxification system is overloaded? The answer is simple. When the liver does not function properly, toxins that we are exposed to accumulate in the body. These toxins affect us in numerous ways, and have damaging effects on many body functions, particularly the immune system, causing chronic health problems. It is not surprising that an overburdened and undernourished liver can be a root cause of many chronic diseases.
Cancers are also thought to be a result of the effects of environmental carcinogens (e.g., cigarette smoke, chemical fumes, toxic exhaust, and airborne particulates), particularly if combined with deficiencies of nutrients required for optimal functioning of the detoxification and immune systems. In a study of chemical plant workers in Turin, Italy, Vineis et al. (1985) analyzed the association of bladder cancer according to occupation (i.e., textiles, leather, printing, dyestuffs, tire and rubber goods production). Highest risks were for the leather, dyestuffs, and tire production industries. An association was found for cancer and the aromatic amines, with the risk being estimated at 10% for those occupations consistently associated with bladder cancer. Vineis et al. (1984) also found that there was a multiplicative effect of relative risks for persons in high-risk occupations who also smoked cigarettes.
Continued . . .