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Liver Degenerative Disease
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
b-oxidation.
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.
How the Liver DetoxifiES
The liver has three main detoxification pathways:
- Filtering the blood to remove large toxins.
- 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.
- 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
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).
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