ALCOHOL AND LIVER DISEASE/HEPATITIS

FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF ALD

Not everyone who drinks alcohol excessively develops ALD. In fact, only about 25 percent of alcoholics develop ALD, and only 10 to 15 percent of alcoholics are found to have cirrhosis during autopsy. So why are some people more likely than others to develop ALD? There is no single answer to this question, as many variables contribute to the development of ALD. The following is a discussion of some of these variables.

Dose and Duration of Alcohol Intake

People who drink large quantities of alcohol over a long period of time are generally at greatest risk of developing ALD. But remember, the alcoholic content differs among different kinds of alcoholic beverages. Therefore, the likelihood of developing ALD is affected by the alcohol content of the beverage ingested, not by the type of alcoholic beverage consumed.

In general, consumption of about 80 grams of alcohol daily for a significant length of time is required for men to develop ALD. 80 grams of alcohol is roughly equivalent to a six-pack of beer or a liter of wine. (To convert grams to ounces multiply by 20 and divide by 567.) Women are much more susceptible to the toxicity of alcohol than are men (see Gender below). It has been estimated that it takes as little as 20 grams of daily alcohol ingestion over an extended period of time for women to develop ALD. The specific length of time it takes for ALD to develop is not known with any precision because so many different factors play a role in its development. Similarly, the amount of time that it takes for cirrhosis to develop is unknown. However, it appears that an average person must drink the above-mentioned amounts of alcohol daily for at least five years in order for cirrhosis to develop. That’s right. A mere five years of excessive drinking puts a person at significant risk for developing cirrhosis! Moreover, remember that the above figures are just estimates and the results may vary depending upon many other factors.

Genetics

Genetics play an important role in the development of ALD. Most people are familiar with the stereotype of the person who “can drink anyone under the table,” or of the easily inebriated person colloquially referred to as a “cheap date.” Well, it has been found that people who fall into the first category are the ones most likely to develop ALD. And the “cheap dates” are the ones least likely to develop ALD. These observations have, at least in part, a genetic basis.

It has been discovered that genetic differences regarding the efficiency of the enzymes (alcohol dehydrogenase and aldehyde dehydrogenase) that establish the rate of the metabolism of alcohol exist among people. Thus, fast metabolizers of alcohol have to drink more than everyone else in order to obtain the desired effects of alcohol. As compared with people who metabolize alcohol at a normal rate, they are less intoxicated after drinking equivalent amounts of alcohol. These people are the ones most likely to develop liver damage, as they are able to consistently consume high levels of alcohol for many years. On the other hand, slow metabolizers of alcohol become rapidly intoxicated when they consume alcohol. These people develop high levels of alcohol in their bloodstreams after consuming only small amounts of liquor. Since these people require relatively minimal quantities of alcohol in order to become intoxicated, they are unlikely to consume alcohol in great enough quantities to develop ALD, and are therefore the least likely ones to develop ALD.

     A similar characteristic is common among Asian people. Certain Asian populations have an impairment of the activity of an enzyme involved in alcohol metabolism- aldehyde dehydrogenase. This impairment results in accumulations of the toxin - acetaldehyde in the body.  Skin flushing, increased heart rate, and severe nausea and vomiting occur in these people when they ingest any alcoholic beverage.  To some extent, this accounts for the low incidence of ALD in the Asian population compared with the United States population.  To take advantage of this reaction, disulfiram (Antabuse) a medication that inhibits aldehyde dehydrogenase and results in acetaldehyde accumulation, is used as a deterrent to consume alcohol.

Genetic markers (specific genes) have been searched for to further explain why certain people are more susceptible to the toxic effects of alcohol on the liver than others. While many candidate genes have been suggested, to date, no specific gene has been proven to directly influence the development of alcoholic liver disease.  However, specific genes located on chromosome #6 are most commonly implicated.

Gender

Gender differences play a role in a person’s susceptibility to the effects of alcohol on the liver. While alcoholism is more common among men, it has been demonstrated that women are more susceptible to the adverse consequences of alcohol on the liver. In fact, women who develop ALD and cirrhosis due to alcohol do so at a younger age than men, and they have consumed a less alcohol in total. It has been noted that women with cirrhosis due to alcohol have a shorter life expectancy than men with cirrhosis due to alcohol.

So why are women so much more susceptible to the toxicity of alcohol than men? Well, the most obvious explanation is that women generally weigh less and are smaller than men. Women on average have a smaller total body area throughout which any ingested alcohol can be distributed. But neither this fact, nor the total amount of alcohol ingested, completely accounts for why women are at a much greater risk of developing ALD. Hormonal differences between men and women have been suggested as a factor.  It has been demonstrated experimentally that female rats are more susceptible to alcohol – induced liver damage than male rats, at least in part because of the higher levels of estrogen- the female sex hormone,  in their bodies. However, this theory has not been proven in humans.   

     Probably the factor that most significantly differentiates the genders is that, as compared with men, many women (not all) have less of the enzyme alcohol dehydrogenase in the lining of their stomachs. This enzyme is the same one that is found in the liver that breaks down alcohol into the byproducts that are less toxic to the liver (see page XX). Thus, the reduced amount of alcohol dehydrogenase enzyme in women increases the likelihood that they will absorb nonmetabolized alcohol from their stomach linings directly into their bloodstreams. Hypothetically, if a man and a woman of equal size and weight each consumes an equivalent amount of alcohol over the same span of time, the woman will have a much higher blood-alcohol level than the man. Once in their bloodstreams, high blood-alcohol levels circulate in their bodies, placing women at increased risk for the toxic effects of alcohol on their livers and other organs.

In addition, studies show that women solicit treatment for alcohol-related problems only half as often as men do. Also, by the time a woman seeks help for her problems, she tends to be sicker and at a more advanced stage of liver disease. It is believed that one reason for this is that women may hide their addictions more successfully than men, and they are not as likely to suffer the adverse social and legal problems due to drinking alcohol. Therefore, their family members, friends, and doctors are less likely to suspect them of alcohol abuse. Studies have shown that after completing treatment in an alcohol rehabilitation program, women return to drinking alcohol more often than men. Unfortunately, statistics indicate that the incidence of alcohol abuse among women is increasing in the United States.

The Presence of Other Liver Diseases

Alcohol has been shown to worsen the course of many liver diseases. Since alcohol is a potential toxin to the liver, people with any type of liver disease should refrain from drinking alcohol.

There appears to be an additive harmful effect to the liver when alcohol is consumed by a person who has one of the hepatitis viruses. Thus, for people with chronic viral hepatitis (see Part Two), consuming alcohol is likely to lead to a worsening of liver disease. In people with hepatitis C, alcohol has been shown to promote the replication of the hepatitis C virus (HCV), thus resulting in elevated hepatitis C viral loads. Furthermore, it has been shown that for people with chronic hepatitis C, consumption of even minimal quantities of alcohol may accelerate the progression of liver disease to cirrhosis. In fact, HCV has been found frequently in people with ALD, especially in those people who have severe liver damage or cirrhosis, suggesting a causative relationship (that is, HCV contributed to the liver damage).

Evidence of infection with the hepatitis B virus (HBV) is more common among alcoholics than the general population. Furthermore, HBV is often found in people with cirrhosis due to ALD. People with ALD who become acutely infected with HBV typically have a much more severe course of infection than people without ALD. Therefore, as with all liver diseases, it is especially important for people with chronic hepatitis B and chronic hepatitis C to refrain from drinking alcohol.

Alcohol can increase iron absorption. Therefore, it is important for people with hemochromatosis and other diseases of iron overload (see Chapter 18) to refrain from consuming alcohol, since alcohol may worsen liver damage. It is important to remember that for any person with liver disease, excessive alcohol consumption doubles (at the very least) the risk of liver cancer.

The Use of Other Drugs

As noted on page XX, the cytochrome P-450 system is one mechanism by which alcohol is broken down. This system is also responsible for the metabolism of a variety of other drugs and medications, some of which are regularly used by people who abuse alcohol. Since these drugs compete for the same pathway as alcohol to be broken down, the capacity of this pathway becomes strained. Thus, toxic levels of these drugs and/or alcohol accumulate in the body. This may lead to additional and often severe liver injury and may account for why some people develop a more rapidly progressive course of ALD than others.

The most well-established alcohol/drug toxicity is caused by the simultaneous use of alcohol with acetaminophen (Tylenol). Typically, one tablet of acetaminophen is 500 milligrams. A therapeutic dose for minor aches and pains can range anywhere from 2 to 6 grams per day (4 to 12 tablets per day). In people without ALD, dosages greater than 7 to 10 grams (typically 15 grams) over a twenty-four hour period may cause liver damage. But for people with ALD, dosages greater than 2 grams over a twenty-four hour period may cause additional and severe liver damage. Therefore, it is crucial for people with ALD to avoid taking more than 4 tablets of acetaminophen within a twenty-four hour period. These people are advised to limit their intake to one to two 500-milligram tablets per twenty-four hour period.

People are often surprised to learn that for people with liver disease, acetaminophen within these limited dosages is actually safer than taking aspirin (ASA) or other nonsteroidal anti-inflammatory drugs (NSAIDs), such as Motrin or Advil. Aspirin and other NSAIDs may cause bleeding disorders (particularly in the gastrointestinal tract) and kidney disorders, in addition to liver injury. Therefore, people with ALD, especially those who already often have a bleeding disorder, should always avoid even small doses of these medications. People should also be aware that other over-the-counter medications, as well as some prescription medicines, may contain acetaminophen or aspirin and other NSAIDs. Therefore, it is important to carefully read the label of any medication prior to taking it. Of course, labels should always be read carefully, and when in doubt, a person should check with his doctor or pharmacist concerning the presence of these substances in a particular medication. Another drug that increases alcohol’s toxic effects on the liver is isoniazid—a drug used to treat tuberculosis. The effect of this drug and others on the liver is discussed in more detail in Chapter 24.

When alcohol is ingested in combination with other medications, it often enhances the effect, and/or side effects of that medication. For example, it may cause excessive sedation (sleepiness) when taken with an anti-anxiety drug, such as alprazolam (Xanax). Or alcohol may increase nausea, vomiting, and severe stomach cramping when taken with certain antibiotics, such as cefaclor (Ceclor). Many drugs such as the H2 blockers - cimetidine (Tagamet) and ranitidine (Zantac), can elevate blood-alcohol levels, thereby resulting in increased alcohol toxicity. A person should always consult with a doctor or pharmacist prior to ingesting alcohol in combination with any other medication.

Lastly, it is important for people with ALD to refrain from using cocaine. The combined ingestion of alcohol and cocaine can accelerate liver injury, and, at high enough levels, this toxic combination has the potential to substantially injure the kidneys and muscles and can even cause death. It is unwise for anyone with any liver disease, or anyone for that matter, to use cocaine, as there is evidence that cocaine, in and of itself, may cause liver injury.

Malnutrition

Poor dietary habits may also contribute to the progression of ALD. In fact, malnutrition—defined by the lack of calories and protein consumed—is noted in almost all people with advanced ALD. Deficiencies of vitamins and minerals are also virtually universal. In people with ALD, these substances are poorly absorbed from the stomach lining as a consequence of alcohol’s harmful effects on the gastrointestinal tract. The prevalence of poor dietary habits in general among people with ALD also accounts for the nutritional deficiencies that they commonly exhibit. See Chapter 23 for some helpful information on diet and nutrition.

Weight

Being overweight has been shown to be a risk factor for the development of another liver disease -  nonalcoholic fatty liver disease (NAFLD) ( see chapter 18). The influence of weight on people with alcoholic liver disease has been evaluated in research studies. It was found that alcoholic people who are overweight are more likely to develop cirrhosis as compared to alcoholic people who are of normal weight.  Therefore, it important that people with ALD maintain normal weight levels. ( see chapter 16 and 23 for more information on normal weight levels).

Diabetes

People with high blood sugar (glucose) levels and/or diabetes, have been found to be at increased risk for developing liver scarring compared with people who have normal sugar levels.  Thus, it is important for people with ALD to maintain low- sugar diets. Those with diabetes should be on sugar-lowering medications.

Other Factors

Some factors which are relevant to ALD come from within the body itself. These include cytokines, endotoxins, free radicals, and possible a form of autoimmune reaction. These factors are discussed below.

Cytokines

Cytokines are substances that are secreted by cells of the immune system. They are involved in regulating the intensity and duration of an immune response. Having a small amount of cytokines present is advantageous, as, at low levels, they play an important role in helping liver cells to repair damage. However, having a large amount of cytokines present is quite dangerous, since at high levels, they play a significant role in causing injury to and death of liver cells. High levels of many cytokines—specifically interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), as well as tumor necrosis factor (TNF)—have frequently been found in people with hepatitis due to alcohol. Thus, the level of cytokines in a person’s body has been shown to play a role in the development of ALD. However, at present, there are no known specific measures that a person can take to alter the amount of cytokines present in his body. This is an area requiring future research.

Endotoxin

Endotoxin is a component of the cell wall of certain types of bacteria. As its name suggests, it is a poisonous substance. Increased levels of endotoxin have been found in people with ALD, and, therefore, endotoxin has been implicated as a possible cause of alcoholic liver injury. In one study, rats were fed alcohol while their endotoxin production was blocked with antibiotics. Their LFTs decreased as did their liver damage. Thus, the use of antibiotics in the treatment of ALD is presently being investigated by researchers.

Free Radicals and Oxidative Stress

Free radicals are toxic, highly reactive compounds that are naturally produced by the body. The number of free radicals increases when the body is exposed to something that it perceives as being hazardous, such as a high-fat diet, cigarette smoke, excess iron, exposure to the sun or excess radiation, and of course, alcohol. One of the more common free radicals produced in response to the ingestion of alcohol is oxygen but in a deformed, toxic state. These radicals are known as oxygen free radicals. Oxygen free radicals can tear through the liver’s protective outer membranes and can cause severe injury and damage. So, the liver, just like a human being, is also subjected to a lot of daily stress. Medically, this is known as oxidative stress. Iron can induce the formation of free radicals. And, in combination with alcohol ingestion, iron may intensify oxidative stress on the liver, leading to greater liver damage. Therefore, people with ALD should avoid taking excess iron. (See Chapter 18 for more information about iron’s effects on the liver.)

As a defense against oxidative stress, the body produces a group of enzymes known as antioxidants that gobble up and render harmless any free radicals they can find. Commonly known antioxidants that the body does not produce include the vitamins A, C, and E. But, probably one of the hardest working antioxidants, and one which is produced by the liver, is called glutathione. In fact, it is believed that one of the ways that alcohol causes liver damage is by interfering with the body’s ability to produce glutathione. Antioxidant therapy for people with ALD is currently undergoing investigation.

Immune Reactions

Some researchers believe that the damage done to the liver by alcohol may be partly attributable to an immune attack upon liver cells, as is the case with autoimmune hepatitis, which was discussed in Chapter 14. Levels of immunoglobulin A (IgA) are commonly found to be elevated in the blood of people with ALD. People with ALD also sometimes have autoantibodies (such as antinuclear antibody [ANA] and smooth muscle antibody [SMA]) in their blood at low titers. Other studies suggest that the production of antibodies against a form of acetaldehyde may be an indicator of the severity of ALD. Further research in this area is expected.

All contents of this article are Copyright © Melissa Palmer, MD

Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).

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