Drinking, Even Casual Amounts, Poses Much Greater Risk for Advanced Liver Disease in HIV/Hepatitis C Patients

News Release May 2, 2014

Penn Medicine Researchers Find Much Stronger Association Between Alcohol Use and Advanced Liver Fibrosis in Patients Compared to Uninfected

PHILADELPHIA — Consumption of alcohol has long been associated with an increased risk of advanced liver fibrosis, but a new study published in the May issue of Clinical Infectious Diseases from researchers at Penn Medicine and other institutions shows that association is drastically heightened in people co-infected with both HIV and chronic hepatitis C virus (HCV) infection.  Even light (“nonhazardous”) drinking—which typically poses a relatively low risk for uninfected persons—was linked to an increased risk of liver fibrosis in the co-infected group.

Reasons for this are not fully understood, but preclinical studies have shown that the two viruses can induce liver cell death and that adding alcohol may accelerate that process and more quickly lead to severe liver fibrosis. Toxicity to the liver from antiretroviral drugs may also be exacerbated by alcohol.

“We’ve shown a much greater risk for coinfected compared to uninfected persons at all levels of alcohol consumption—from nonhazardous drinking up to hazardous/binge drinking and abuse/dependence,” said senior author Vincent Lo Re III, MD, MSCE, assistant professor of Medicine and Epidemiology in the division of Infectious Diseases and department of Biostatistics and Epidemiology at Penn and an infectious disease physician at the Veteran Affairs Medical Center in Philadelphia. “This highlights how important it is for clinicians to be counseling co-infected patients on reducing alcohol consumption. More communication and education about the risks of alcohol may prompt patients to reduce drinking or quit altogether, which will help reduce the incidence of complications.”

Few studies have investigated the association between alcohol and liver disease in HIV/HCV-co-infected patients, and none have compared risks to uninfected persons.

For the study, researchers, which included first author Joseph K. Lim, MD, of the Yale University School of Medicine and the Veterans Affairs Connecticut Healthcare System, conducted a cross-sectional study among 7,270 participants from the Veterans Aging Cohort Study: 701 HIV/HCV co-infected; 1,410 HIV-mono-infected; 296 HCV-mono-infected; and 1,158 uninfected.  Alcohol use was determined by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire and diagnoses of alcohol abuse/dependence and classified as nonhazardous drinking, hazardous/binge drinking, and alcohol-related diagnosis.

The team found that regardless of HIV or HCV status, the prevalence of advanced hepatic fibrosis increased as alcohol use category increased. However, the strongest associations were observed in co-infected patients across all alcohol categories compared with uninfected non-hazardous drinkers. 

Co-infected individuals with nonhazardous drinking were 13 times more likely to have advanced liver fibrosis than uninfected persons who reported non-hazardous drinking.  Co-infected patients with a history of hazardous/binge drinking were 17 times more likely, whereas those who had alcohol-related diagnosis were 21 times more likely, to have advanced liver fibrosis compared to their uninfected non-hazardous drinking counterparts.

“The difference between co-infected and uninfected groups was stark. Given the prevalence of drinking in co-infected individuals, it is important to determine the patterns of alcohol use, such as nonhazardous drinking and even binge drinking, which are not traditionally thought to contribute to liver fibrosis,” said Lo Re.

Other researchers from the study include researchers from the US Food and Drug Administration; North Shore–LIJ School of Medicine; National Institute on Alcohol Abuse and Alcoholism; University of Pittsburgh and Pittsburgh VA Medical Center; VA Medical Center and George Washington University Medical Center;  Atlanta VA Medical Center and Emory University School of Medicine; VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA; and McGill University Health Centre.

The study was support in part by the National Institute of Allergy and Infectious Diseases (K01 AI070001 to Dr. Lo Re).

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

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Alcohol-linked deaths a problem for the Americas

Elizabeth DeVita-Raebrun
Reuters
3:05 p.m. CST, February 4, 2014

NEW YORK (Reuters Health) - Liver disease and brain disorders due to alcohol abuse are important causes of premature death in the Americas, a new study concludes.

The toll of too much drinking is especially high among men and among middle-aged people, according to the report, whose authors say it's the first to tabulate deaths resulting solely from alcohol.

"This provides direct evidence of the impact of alcohol on the health of countries in the region," said one of the study's authors, Dr. Vilma Pinheiro Gawryszewski, an advisor on health information and analysis for the Pan American Health Organization(PAHO).

In the 16 North, Central, and South American countries studied, alcohol was the sole cause of 79,456 deaths a year, the researchers say. That represented 1.4 percent of deaths from all causes, and alcohol-related liver disease alone accounted for 0.6 percent of all-cause mortality.

The study was based on data collected between 2007 and 2009 for countries in the PAHO mortality database.

The researchers excluded deaths from vehicle accidents and other fatal situations where alcohol might have been involved but there could also have been other causes.

Looking just at deaths due directly to alcohol, they found 63 percent were from liver disease and 32 percent were from neurological and psychiatric conditions grouped under "degeneration of the brain and nervous system."

Other listed causes of death included alcohol poisoning, alcohol-linked heart and gastric problems and fetal alcohol syndrome.

The death toll is the "tip of the iceberg," meaning that there are probably many more alcohol-related deaths that the researchers were not able to identify, said another of the study's authors, Dr. Maristela Monteiro, regional advisor on alcohol and substance abuse at PAHO.

Monteiro said that raising the price of alcohol and increasing taxes would help to prevent some of these deaths. Many countries have found these steps effective in controlling tobacco use, but such measures have not been used to control alcohol consumption, she said.

Even the U.S., which was included in the study, has not done as much as it could, said David Jernigan, director of the Center on Alcohol Marketing and Youth at Johns Hopkins Bloomberg School of Public Health.

"The single most efficient thing you can do is to raise taxes," Jernigan told Reuters Health. "Many states haven't raised it in decades. That means the price doesn't go up with inflation, and alcohol gets cheaper every year."

And while the U.S. and other countries have limited tobacco advertising, alcohol advertising "is virtually everywhere," he said.

Mortality due to alcohol was highest in El Salvador, Guatemala and Nicaragua, with death rates of 27.4, 22.3 and 21.3 per 100,000 people, respectively. These were also the countries with the highest consumption of hard liquor, the authors noted.

Colombia, Argentina and Canada had the lowest death rates attributable to alcohol at 1.8, 4.0 and 5.7 per 100,000, respectively. The alcohol death rate in the United States was "intermediate," at 6.7 per 100,000, Monteiro said.

Men accounted for 84 percent of the deaths overall, but that proportion was not the same in all countries. The risk of a man dying from alcohol in El Salvador was nearly 30 times higher than that of a woman, but only about three times higher in Canada and the U.S.

People in the mid-to-late 50s and 60s age range were at the highest risk. This later in life risk, Jernigan said, points to the long-term impact of heavy drinking.

"Mostly in this country, we talk about alcohol and the risk for the young," in whom drunk driving, violence, and accidents are important causes of death, Jernigan said. "This really shows the impact over the life course."

Despite the grim statistics, Jernigan says studies like this one are a positive sign.

"On one hand, you could say, 'this is a huge problem, and not enough is being done.' On the other," he said, "you could say, 'we're getting better at documenting it and showing that, until we take meaningful action, it's not going to go away.'"

In poorer countries, other factors contributing to the deaths could include infectious diseases that hasten the course of liver disease, as well as poor nutrition and limited access to health services.

"In the U.S., people wouldn't wait until they were too sick for help to seek out services, because treatment is available," said Monteiro. That is not always the case, she said, in other countries.

Source: http://bit.ly/1enwJIT Addiction, online January 14, 2014.

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Most U.S. doctors fail to discuss alcohol with patients: study

BY DAVID BEASLEY

ATLANTA Tue Jan 7, 2014 2:53pm EST

Bottles showing the barrel aging process are seen at the Jack Daniel's distillery in Lynchburg, Tennessee May 10, 2011.

CREDIT: REUTERS/ MARTINNE GELLER

(Reuters) - Doctors are failing to find out if their patients drink too much alcohol, despite evidence that at least 38 million American adults consume an excessive amount, a U.S. health agency said on Tuesday.

An estimated 88,000 people die in the United States each year from drinking too much alcohol, but only one out of six adults overall and one in four binge drinkers have discussed their drinking habits with their doctors, according to a new study by the Centers for Disease Control and Prevention (CDC).

That practice needs to change, CDC Director Thomas Frieden said.

"It should be a part of routine patient care," Frieden said. "In the same way we screen patients for high blood pressure, high cholesterol, we should be screening for excess alcohol use."

The study's findings were based on 166,000 interviews in 44 states and the District of Columbia in 2011. The percentage of patients who had ever discussed their drinking with a health care provider ranged from a low of 8.7 percent in Kansas to 25.5 percent in Washington, D.C.

Doctors are often too busy to screen patients for alcohol abuse and may view treatment options as ineffective, the CDC said.

But asking patients about their alcohol use and then offering advice on how to reduce it, or referring the most serious cases for specialized treatment, can be effective in many cases, Frieden said.

"Counseling for five, 10, 15 minutes can result in a substantial reduction in problem drinking," he said.

Drinking too much can increase chances of heart disease, liver damage, breast cancer and other health problems, the CDC said.

The CDC defines binge drinking as five or more drinks in a few hours for men and four or more for women. Adult men should average no more than two drinks a day and women no more than one daily, the health agency said.

The federal Affordable Care Act of 2010 requires new insurance plans to cover alcohol screening with no patient co-pay, Frieden said.

(Editing by Colleen Jenkins and Chris Reese)

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Acetaminophen and Alcohol May Be Nephrotoxic

Medscape Medical News > Conference News

Neil Osterweil
November 15, 2013

BOSTON, Massachusetts — The link between acetaminophen (Tylenol and generics) and liver damage is well established, but there is also evidence to suggest that in some asymptomatic patients, therapeutic doses of acetaminophen and light-to-moderate alcohol use can lead to renal disease.

An examination of data from a nationwide health survey found that taken alone, neither light-to-moderate alcohol consumption nor acetaminophen were associated with significant risk for kidney disease. But respondents who reported taking both acetaminophen and drinking lightly or moderately had a more than two-fold higher risk for kidney dysfunction.

"Although individually it may not be harmful to ingest therapeutic doses of acetaminophen and light to moderate amounts of alcohol, we found that combining the two has the potential to be hazardous," said Harrison Ndetan, MSc, MPH, DrPH, from Parker University in Dallas, Texas, at the American Public Health Association 141st annual meeting here.

The findings suggest that primary care practitioners who treat patients with acute and chronic pain should inform them of the potential for kidney problems with concomitant use of alcohol and over-the-counter (OTC) analgesics containing acetaminophen, he told Medscape Medical News.

Pain is among the most common symptoms seen in primary practice, and an estimated 36 million Americans self-medicate with OTC analgesics, of which acetaminophen-containing products are the most frequently used, Dr, Ndetan said.

Acetaminophen has been shown to have nephrotoxic effects when used above recommended doses, and alcohol is known to affect renal filtration protein transporters that can affect acetaminophen metabolism, he said.

Alcohol and Analgesics

To see whether alcohol might exacerbate the renal effects of the drug when both are used in moderation, Dr. Ndetan and colleagues examined data from the 2003-2004 iteration of the National Health and Nutrition Examination Survey (NHANES).

Among more than 10,000 respondents included in the analysis, 38.13% reported mild-to-moderate alcohol consumption, 5.6% reported using therapeutic doses of acetaminophen, and 2.6% reported using both. In all, 1.2% of respondents reported renal dysfunction.

In logistic regression analyses controlling for sociodemographics and health conditions, the authors found that the combination but not acetaminophen or alcohol alone was associated with significant risk for kidney dysfunction (see table).

Table. Risk for Renal Dysfunction, NHANES 2003 - 2004

Variable	Odds Ratio	95% Confidence Interval
Therapeutic acetaminophen (1.2 g)	0.91	0.57 - 1.45
Light/moderate alcohol	0.53	0.43 - 0.65
Acetaminophen and alcohol	2.23	1.22 - 4.08

The risk for kidney dysfunction in respondents who mixed acetaminophen and alcohol was greater for older adults, males, blacks, and Hispanics (vs, whites), and those with conditions that may compromise renal function, such as hypertension, diabetes, and obesity.

Jeanmarie Perrone, MD, associate professor of emergency medicine and director of medical toxicology at the University of Pennsylvania in Philadelphia told Medscape Medical News that acetaminophen-induced nephrotoxicty typically manifests as renal insufficiency in about 1% - 2% of patients who present with acetaminophen overdose. Although it is not as well documented as acetaminophen hepatoxicity, it is not all that uncommon.

Dr. Perrone is coauthor of a study of the pathophysiology, clinical presentation, and management of acetaminophen-induced nephrotoxicity. She notes that chronic alcohol use as well as certain drugs (eg, anticonvulsants) are associated with increased activity of the cytochrome P450 (CYP-450) pathway, and that CYP-450 can enhance acetaminophen toxicity (J Med Toxicol. 2008;Mar 4(1):2-6).

The study funding source was not reported. Dr. Ndetan and Dr. Perrone have disclosed no relevant financial relationships.

American Public Health Association (APHA) 141st Annual Meeting: Abstract 290307. Presented November 4, 2013.

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Alcohol and Cancer Risk (Fact Sheet)

Provided by OncologyNurseAdvisor

October 28, 2013

What is alcohol?

Alcohol is the common term for ethanol or ethyl alcohol, a chemical substance found in beer, wine, and liquor, as well as in some medicines, mouthwashes, household products, and essential oils (scented liquids taken from plants). Alcohol is produced by the fermentation of sugars and starches by yeast.

The main types of alcoholic drinks and their alcohol content are as follows:

• Beers and hard ciders: 3-7 percent alcohol
• Wines, including sake: 9-15 percent alcohol
• Wines fortified with liquors, such as port: 16-20 percent alcohol

Liquor, or distilled spirits, such as gin, rum, vodka, and whiskey, which are produced by distilling the alcohol from fermented grains, fruits, or vegetables: usually 35-40 percent alcohol (70-80 proof), but can be higher

According to the National Institute on Alcohol Abuse and Alcoholism, a standard alcoholic drink in the United States contains 14.0 grams (0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in

• 12 ounces of beer
• 8 ounces of malt liquor
• 5 ounces of wine
• 1.5 ounces or a "shot" of 80-proof liquor

The federal government's Dietary Guidelines for Americans 2010 defines moderate alcohol drinking as up to one drink per day for women and up to two drinks per day for men. Heavy alcohol drinking is defined as having more than three drinks on any day or more than seven drinks per week for women and more than four drinks on any day or more than 14 drinks per week for men.

What is the evidence that alcohol drinking is a cause of cancer?

Based on extensive reviews of research studies, there is a strong scientific consensus of an association between alcohol drinking and several types of cancer (1, 2). In its Report on Carcinogens, the National Toxicology Program of the US Department of Health and Human Services lists consumption of alcoholic beverages as a known human carcinogen. The research evidence indicates that the more alcohol a person drinks—particularly the more alcohol a person drinks regularly over time—the higher his or her risk of developing an alcohol-associated cancer. Based on data from 2009, an estimated 3.5 percent of all cancer deaths in the United States (about 19,500 deaths) were alcohol related (3).

Clear patterns have emerged between alcohol consumption and the development of the following types of cancer:

• Head and neck cancer: Alcohol consumption is a major risk factor for certain head and neck cancers, particularly cancers of the oral cavity (excluding the lips), pharynx (throat), and larynx (voice box) (4). People who consume 50 or more grams of alcohol per day (approximately 3.5 or more drinks per day) have at least a two to three times greater risk of developing these cancers than nondrinkers (4). Moreover, the risks of these cancers are substantially higher among persons who consume this amount of alcohol and also use tobacco (5).

• Esophageal cancer: Alcohol consumption is a major risk factor for a particular type of esophageal cancer called esophageal squamous cell carcinoma (2). In addition, people who inherit a deficiency in an enzyme that metabolizes alcohol have been found to have substantially increased risks of alcohol-related esophageal squamous cell carcinoma (see

• Liver cancer: Alcohol consumption is an independent risk factor for, and a primary cause of, liver cancer (hepatocellular carcinoma) (6). (Chronic infection with hepatitis B virus and hepatitis C virus are the other major causes of liver cancer.)

• Breast cancer: More than 100 epidemiologic studies have looked at the association between alcohol consumption and the risk of breast cancer in women. These studies have consistently found an increased risk of breast cancer associated with increasing alcohol intake. A meta-analysis of 53 of these studies (which included a total of 58,000 women with breast cancer) showed that women who drank more than 45 grams of alcohol per day (approximately three drinks) had 1.5 times the risk of developing breast cancer as nondrinkers (a modestly increased risk) (7). The risk of breast cancer was higher across all levels of alcohol intake: for every 10 grams of alcohol consumed per day (slightly less than one drink), researchers observed a small (7 percent) increase in the risk of breast cancer. 

The Million Women Study in the United Kingdom (which included more than 28,000 women with breast cancer) provided a more recent, and slightly higher, estimate of breast cancer risk at low to moderate levels of alcohol consumption: every 10 grams of alcohol consumed per day was associated with a 12 percent increase in the risk of breast cancer (8).

• Colorectal cancer: Alcohol consumption is associated with a modestly increased risk of cancers of the colon and rectum. A meta-analysis of 57 cohort and case-control studies that examined the association between alcohol consumption and colorectal cancer risk showed that people who regularly drank 50 or more grams of alcohol per day (approximately 3.5 drinks) had 1.5 times the risk of developing colorectal cancer as nondrinkers or occasional drinkers (9). For every 10 grams of alcohol consumed per day, there was a small (7 percent) increase in the risk of colorectal cancer.

Research on alcohol consumption and other cancers:

Numerous studies have examined the association between alcohol consumption and the risk of other cancers, including cancers of the pancreas, ovary, prostate, stomach, uterus, and bladder. For these cancers, either no association with alcohol use has been found or the evidence for an association is inconsistent. 

However, for two cancers—renal cell (kidney) cancer and non-Hodgkin lymphoma (NHL)—multiple studies have shown that increased alcohol consumption is associated with a decreased risk of cancer (10, 11). A meta-analysis of the NHL studies (which included 18,759 people with NHL) found a 15 percent lower risk of NHL among alcohol drinkers compared with nondrinkers (11). The mechanisms by which alcohol consumption would decrease the risks of either renal cell cancer or NHL are not understood.

How does alcohol increase the risk of cancer?

Researchers have identified multiple ways that alcohol may increase the risk of cancer, including:

• ametabolizing (breaking down) ethanol in alcoholic drinks to acetaldehyde, which is a toxic chemical and a probable human carcinogen; acetaldehyde can damage both DNA (the genetic material that makes up genes) and proteins (see Question 5)
• generating reactive oxygen species (chemically reactive molecules that contain oxygen), which can damage DNA, proteins, and lipids (fats) through a process called oxidation
• impairing the body's ability to break down and absorb a variety of nutrients that may be associated with cancer risk, including vitamin A; nutrients in the vitamin B complex, such as folate; vitamin C; vitamin D; vitamin E; and carotenoids
• increasing blood levels of estrogen, a sex hormone linked to the risk of breast cancer

Alcoholic beverages may also contain a variety of carcinogenic contaminants that are introduced during fermentation and production, such as nitrosamines, asbestos fibers, phenols, and hydrocarbons.

How does the combination of alcohol and tobacco affect cancer risk?

Epidemiologic research shows that people who use both alcohol and tobacco have much greater risks of developing cancers of the oral cavity, pharynx (throat), larynx, and esophagus than people who use either alcohol or tobacco alone. In fact, for oral and pharyngeal cancers, the risks associated with using both alcohol and tobacco are multiplicative; that is, they are greater than would be expected from adding the individual risks associated with alcohol and tobacco together (5, 12).

Can a person's genes affect their risk of alcohol-related cancers?

A person's risk of alcohol-related cancers is influenced by their genes, specifically the genes that encode enzymes involved in metabolizing (breaking down) alcohol (13).

For example, one way the body metabolizes alcohol is through the activity of an enzyme called alcohol dehydrogenase, or ADH. Many individuals of Chinese, Korean, and especially Japanese descent carry a version of the gene for ADH that codes for a "superactive" form of the enzyme. This superactive ADH enzyme speeds the conversion of alcohol (ethanol) to toxic acetaldehyde. As a result, when people who have the superactive enzyme drink alcohol, acetaldehyde builds up. Among people of Japanese descent, those who have this superactive ADH have a higher risk of pancreatic cancer than those with the more common form of ADH (14).

Another enzyme, called aldehyde dehydrogenase 2 (ALDH2), metabolizes toxic acetaldehyde to non-toxic substances. Some people, particularly those of East Asian descent, carry a variant of the gene for ALDH2 that codes for a defective form of the enzyme. In people who have the defective enzyme, acetaldehyde builds up when they drink alcohol. The accumulation of acetaldehyde has such unpleasant effects (including facial flushing and heart palpitations) that most people who have inherited the ALDH2 variant are unable to consume large amounts of alcohol. Therefore, most people with the defective form of ALDH2 have a low risk of developing alcohol-related cancers.

However, some individuals with the defective form of ALDH2 can become tolerant to the unpleasant effects of acetaldehyde and consume large amounts of alcohol. Epidemiologic studies have shown that such individuals have a higher risk of alcohol-related esophageal cancer, as well as of head and neck cancers, than individuals with the fully active enzyme who drink comparable amounts of alcohol (15). These increased risks are seen only among people who carry the ALDH2 variant and drink alcohol—they are not observed in people who carry the variant but do not drink alcohol.

Can drinking red wine help prevent cancer?

Researchers conducting studies using purified proteins, human cells, and laboratory animals have found that certain substances in red wine, such as resveratrol, have anticancer properties (16). Grapes, raspberries, peanuts, and some other plants also contain resveratrol. However, clinical trials in humans have not provided evidence that resveratrol is effective in preventing or treating cancer (17). Few epidemiologic studies have looked specifically at the association between red wine consumption and cancer risk in humans. 

What happens to cancer risk after a person stops drinking alcohol?

Most of the studies that have examined whether cancer risk declines after a person stops drinking alcohol have focused on head and neck cancers and on esophageal cancer. In general, these studies have found that stopping alcohol consumption is not associated with immediate reductions in cancer risk; instead, it may take years for the risks of cancer to return to those of never drinkers.

For example, a pooled analysis of 13 case-control studies of cancer of the oral cavity and pharynx combined found that alcohol-associated cancer risk did not begin to decrease until at least 10 years after stopping alcohol drinking. Even 16 years after they stopped drinking alcohol, the risk of cancer was still higher for ex-drinkers than for never drinkers (18).

In several studies, the risk of esophageal cancer was also found to decrease slowly with increasing time since stopping alcohol drinking. A pooled analysis of five case–control studies found that the risk of esophageal cancer did not approach that of never drinkers for at least 15 years after stopping alcohol drinking (18).

Is it safe for someone to drink alcohol while undergoing cancer chemotherapy?

As with most questions related to a specific individual's cancer treatment, it is best for a patient to check with their health care team about whether or not it is safe to drink alcohol during or immediately following chemotherapy treatment. The doctors and nurses administering the treatment will be able to give specific advice about whether drinking alcohol is safe with particular chemotherapy drugs and/or other medications prescribed along with chemotherapy.

Selected References

1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate Exit Disclaimer. IARC Monographs on the Evaluation of Carcinogenic Risks in Humans 2010;96:3-1383.

2. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens. Exit Disclaimer IARC Monographs on the Evaluation of Carcinogenic Risks in Humans 2012;100(Pt E):373-472.

3. Nelson DE, Jarman DW, Rehm J, et al. Alcohol-attributable cancer deaths and years of potential life lost in the United States. American Journal of Public Health 2013;103(4):641-648.

4. Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic beverages Exit Disclaimer. Lancet Oncology 2007;8(4):292-293.

5. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiology, Biomarkers & Prevention 2009;18(2):541-550.

6. Grewal P, Viswanathen VA. Liver cancer and alcohol. Clinics in Liver Disease 2012;16(4):839-850.

7. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. British Journal of Cancer 2002;87(11):1234-1245.

8. Allen NE, Beral V, Casabonne D, et al. Moderate alcohol intake and cancer incidence in women. Journal of the National Cancer Institute 2009;101(5):296-305.

9. Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Annals of Oncology 2011;22(9):1958-1972.

10. Bellocco R, Pasquali E, Rota M, et al. Alcohol drinking and risk of renal cell carcinoma: results of a meta-analysis. Annals of Oncology 2012;23(9):2235-2244.

11. Tramacere I, Pelucchi C, Bonifazi M, et al. A meta-analysis on alcohol drinking and the risk of Hodgkin lymphoma. European Journal of Cancer Prevention 2012;21(3):268-273.

12. Turati F, Garavello W, Tramacere I, et al. A meta-analysis of alcohol drinking and oral and pharyngeal cancers: results from subgroup analyses. Alcohol and Alcoholism 2013;48(1):107-118.

13. Druesne-Pecollo N, Tehard B, Mallet Y, et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncology 2009;10(2):173-180.

14. Kanda J, Matsuo K, Suzuki T, et al. Impact of alcohol consumption with polymorphisms in alcohol-metabolizing enzymes on pancreatic cancer risk in Japanese. Cancer Science 2009;100(2):296-302.

15. Yokoyama A, Omori T. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers Exit Disclaimer. Alcohol 2005;35(3):175-185.

16. Athar M, Back JH, Tang X, et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology 2007;224(3):274-283.

17. Patel KR, Scott E, Brown VA, et al. Clinical trials of resveratrol. Annals of the New York Academy of Sciences 2011;1215:161-169.

18. Rehm J, Patra J, Popova S. Alcohol drinking cessation and its effect on esophageal and head and neck cancers: a pooled analysis. International Journal of Cancer 2007;121(5):1132-1137.

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Bermuda Triangle for the liver: Alcohol, obesity, and viral hepatitis

Journal of Gastroenterology and Hepatology

Special Issue: 7th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis. Funding for this conference was made possible (in part) by Grant 5 R13AA20691-02 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Guest Editors: Bin Gao and Fu-Sheng Wang

Volume 28, Issue Supplement S1, pages 18–25, August 2013

Review

Samir Zakhari

Article first published online: 15 JUL 2013

DOI: 10.1111/jgh.12207

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: Alcohol; viral hepatitis; liver; oxidative stress; free radicals; CYP2E1

Abstract

Despite major progress in understanding and managing liver disease in the past 30 years, it is now among the top 10 most common causes of death globally. Several risk factors, such as genetics, diabetes, obesity, excessive alcohol consumption, viral infection, gender, immune dysfunction, and medications, acting individually or in concert, are known to precipitate liver damage. Viral hepatitis, excessive alcohol consumption, and obesity are the major factors causing liver injury. Estimated numbers of hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected subjects worldwide are staggering (370 and 175 million, respectively), and of the 40 million known human immunodeficiency virus positive subjects, 4 and 5 million are coinfected with HBV and HCV, respectively. Alcohol and HCV are the leading causes of end-stage liver disease worldwide and the most common indication for liver transplantation in the United States and Europe. In addition, the global obesity epidemic that affects up to 40 million Americans, and 396 million worldwide, is accompanied by an alarming incidence of end-stage liver disease, a condition exacerbated by alcohol. This article focuses on the interactions between alcohol, viral hepatitis, and obesity (euphemistically described here as the Bermuda Triangle of liver disease), and discusses common mechanisms and synergy.

The global burden

Liver cirrhosis and hepatocellular carcinoma (HCC) represent end-stage liver disease (ESLD) and thus are associated with mortality. Globally, the incidence and prevalence of liver cirrhosis vary markedly based largely on the causative factors. In the developed world, alcohol, hepatitis C virus (HCV), and nonalcoholic steatohepatitis are the leading causes of cirrhosis, whereas viral hepatitis (especially hepatitis B virus [HBV]) is considered the leading cause in developing countries. Data from 2001 indicate that in developed countries, cirrhosis was the sixth most common cause of death among adults, and in developing countries, it claimed 320 000 lives, ranking as the ninth most common cause of death. In the European Union alone, approximately 29 million individuals suffer from chronic liver disease of whom 170 000 and 47 000 die annually from cirrhosis and liver cancer, respectively.[1] In the United States, approximately 46 700 individuals died from liver cirrhosis and cancer in 2002.[2] HBV and HCV infection are major causes of morbidity and mortality. According to World Health Organization, an estimated 2 billion people have been infected with HBV, and more than 240 million have chronic liver infections worldwide. About 600 000 people die every year from the acute or chronic consequences of HBV infection, which is endemic in China and other parts of Asia, where most people become infected during childhood; 8–10% of the adult population is chronically infected. HBV-induced liver cancer is among the top three causes of death from cancer in men, and a major cause of cancer in women in this region. Globally, cirrhosis attributable to HBV or HCV accounted for 30% and 27%, respectively, and HCC was attributable to HBV (53%) or HCV (25%). Applied to 2002 worldwide mortality estimates, chronic HBV and HCV infections represent 929 000, including 446 000 cirrhosis deaths (HBV: 235 000; HCV: 211 000) and 483 000 liver cancer deaths (HBV: 328 000; HCV: 155 000).[3]

Nonalcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver damage including steatosis, steatohepatitis, fibrosis, and cirrhosis in patients who do not consume large amount of alcohol.[4] NAFLD is a significant factor for serious liver disease because of its rising prevalence in the general population,[5] and the potential to progress to ESLD and HCC.[6] NAFLD commonly occurs in patients with obesity, diabetes, and hyperlipidemia. In the past two decades, obesity in North America has more than doubled and continues to rise worldwide. In 2005, 8% of men and 12% of women were obese. By 2030, the number of obese adults globally is projected to be 573 million individuals.[7]

The combination of chronic heavy alcohol consumption, viral hepatitis infection, and obesity represent a major assault on liver's health worldwide.

Alcoholic liver disease (ALD)

Chronic alcohol consumption results in liver disease which varies extensively between individuals in severity and progression for comparable levels of alcohol consumption. This variability could be attributed to variations in the expression and activity of individual isoforms of the alcohol-metabolizing enzymes: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), but is also influenced by variations in patterns of alcohol intake (binge vs chronic drinking), nutritional status, gender, smoking, or abuse of other drugs. In addition, the onset and severity of ALD is strongly influenced by other comorbid conditions such as obesity or HCV infection. This increase in susceptibility to ALD is not due solely to intrahepatic factors, but may also involve alcohol-induced changes in other tissues, such as adipose tissue, central nervous system, the gut, and the immune system. Factors contributing to alcohol-induced liver disease are thus complex and systemic.[8] The spectrum of ALD includes:

1. Fatty liver (hepatic steatosis), characterized histologically by lipid droplets in hepatocytes. This condition is usually reversible upon cessation of alcohol consumption, and thus is thought to be a relatively innocuous side effect of heavy drinking. However, hepatic steatosis often develops in obesity, metabolic syndrome, and type 2 diabetes, clinical conditions that involve significant metabolic defects. Thus, fatty liver by itself reflects a condition of metabolic stress that is a risk factor for the development of more severe forms of liver disease.
2. Alcoholic hepatitis, an inflammatory condition characterized by significantly increased serum levels of liver enzymes (alanine aminotranferease and aspartate aminotransferase) and moderate to severe tissue damage, including necrotic foci with neutrophil infiltration. Acute alcoholic hepatitis is a potentially fatal disease that develops in a significant fraction (30–40%) of chronic heavy drinkers.
3. Liver fibrosis/cirrhosis, about 10–15% of chronic heavy drinkers proceed to develop fibrosis and cirrhosis.
4. HCCs occur in about 2% of cirrhotic patients.

Although factors that facilitate the development of hepatitis and cirrhosis are not well characterized, impairment in the cellular stress defense mechanisms, (e.g. oxidative stress),[9] or derailment of the balance of autocrine or paracrine mediators that are critical in maintaining normal homeostatic conditions are documented. In addition, chronic alcohol consumption interferes with liver regeneration, which under normal conditions is a highly effective repair mechanism that avoids scar tissue formation.

Mechanisms of ALD

Various mechanisms have been identified for ALD (Fig. 1) which are involved at various stages of progression.

Figure 1. Known mechanisms of alcoholic liver damage. CB, cannabinoid receptor; ER, endoplasmic reticulum; Fe, Ferrous molecule; HCC, hepatocellular carcinoma; HNE, 4-hydroxynonenal; HSC, hepatic stellate cell; KC, Kupffer cells; LPS, lipopolysaccharide; MAA, malondialdehyde-acetaldehyde adduct; MDA, malondialdehyde; Mt GSH, mitochondrial glutathione; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; ROS, reactive oxygen species; TGF, transforming growth factor.

Fatty liver

Both intrahepatic and extrahepatic mechanisms are involved in hepatic steatosis:

a) Intrahepatic factors

Hepatic steatosis due to heavy alcohol consumption has been attributed to a metabolic stress imposed by the fact that the liver is the predominant site of ethanol metabolism. Possible mechanisms include: (i) suppression of mitochondrial fatty acid β-oxidation; (ii) a limitation in the permeability of the outer mitochondrial membrane pore protein voltage-dependent anion-selective channel;[10] (iii) enhancement of hepatic uptake of free fatty acids from the circulation; (iv) increase in de novo synthesis of fatty acids and triglycerides; and (v) derailment of lipoprotein synthesis and secretion.

Chronic alcohol consumption induces a marked increase in cytochrome P450 2E1 (CYP2E1) activity, with a resultant increased demand for nicotinamide adenine dinucleotide phosphate (NADPH), an increased rate of formation of reactive oxygen species (ROS), and a decrease in oxidative stress defense capacity. At the same time, impairment of mitochondrial respiratory capacity caused by defects in the electron transport and ATP synthase complexes results in further increase in ROS formation at the mitochondrial level.[11] The ethanol-induced stress is further exacerbated by defects in the methionine cycle, resulting in a decrease in glutathione (GSH) synthesis, which contributes to the decline in oxidative stress defenses. Importantly, these conditions also reflect an increase in endoplasmic reticulum (ER) stress, a common response do the accumulation of defective proteins.[12] The resulting accumulation of stress conditions in hepatocytes causes an increased susceptibility to cell death signals. Accompanying the structural and functional changes in subcellular organelles, chronic ethanol treatment results in significant changes in the profile of transcription factors that regulate lipid homeostasis in the liver. Ethanol consumption elicits a decrease in peroxisome proliferator-activated receptor (PPAR)-α activity, thereby suppressing the catabolic lipid metabolic pathways, including peroxisomal and mitochondrial fatty acid oxidation. At the same time, ethanol increases the activity of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which enhances lipid synthetic pathways. In addition, there has been some evidence that the adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited by ethanol. However, it is difficult to distinguish direct and indirect effects of ethanol. For instance, AMPK activity in the liver is regulated not only by the availability of AMP in the cell, but also responds to extracellular signals, including the adipose tissue derived cytokine adiponectin.

A related regulatory pathway affected by ethanol may involve the deacetylase silent information regulator-1 (SIRT-1), which requires activation by nicotinamide adenine dinucleotide (NAD⁺). Thus, the change in NAD redox state in the liver during ethanol oxidation may facilitate inhibition of SIRT-1. It has been reported that SIRT-1 activity in the liver of mice is decreased after ethanol treatment.[13] Among the targets of SIRT-1 are several key regulators of lipid metabolism, including the transcriptional coregulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Its deacetylation by SIRT-1 allows it to stimulate gene expression through its interactions with PPAR-α. Furthermore, SREBP-1c is a target for SIRT-1 and its acetylation state may affect its transcriptional activity.

b) Extrahepatic factors

Lipid metabolism in the liver is integrated with a variety of signals, including circulating hormones, cytokines, nutrition, and other factors that impinge on the intrahepatic processes leading to steatosis. While some of these factors are intrahepatic (e.g. cytokines released from Kupffer cells, endothelial cells, or stellate cells), others are dispatched by remote tissues. Of particular relevance are hormones (e.g. insulin), adiponectin and leptin (secreted from adipose tissue), and stress hormones and satiety factors that act through the hypothalamus or other brain structures to regulate food intake. Chronic ethanol consumption has a notable impact on the synthesis and secretion of several of these factors, in addition to affecting their capacity to impact lipid metabolic pathways in the liver.

Adiponectin, one of the adipokines secreted by adipose tissue to regulate lipid homeostasis, acts on multiple tissues including the liver to sensitize the response to insulin and enhance fatty acid oxidation. In animal experiments, ethanol feeding tends to suppress adiponectin secretion from adipose tissue. However, the effects of ethanol on adiponectin levels may depend on dietary factors such as the content of saturated and unsaturated fat.[14] Whether circulating adiponectin levels are similarly correlated with liver damage in human alcoholics remains unclear.[15]

Insulin plays a dominant role in integrating fatty acid and carbohydrate metabolism in the liver with the energetic needs of other tissues. Nonalcoholic hepatic steatosis that occurs in the metabolic syndrome and type II diabetes is commonly associated with insulin resistance, that is, a decreased capacity to respond to changes in circulating insulin, in multiple tissues including liver and muscle. There is strong evidence that stress responses mediated by free fatty acid accumulation or ER stress result in activation of stress response protein kinases, including protein kinase C and Jun-N-terminal kinase, which affect the intracellular signaling pathways through which insulin exerts its effects.

Alcoholic hepatitis

As described earlier, hepatic steatosis represents a severe condition of increased oxidative stress, ER, and metabolic stress. However, the mechanisms by which such stress conditions can lead to a more severe inflammatory condition remain only partly understood. Increased cell death (by necrosis or apoptosis) sets in motion further pro-inflammatory responses in the liver by producing cytokines and chemokines that help mobilize neutrophils and other inflammatory cells that further enhance liver damage. Also, it appears that overproduction of ROS by the damaged mitochondria could play a salient role. Factors that may be involved in the precipitation of alcoholic hepatitis are briefly discussed later.

Oxidative alcohol metabolism in the liver

Only about 2–10% of the absorbed alcohol is eliminated via the lungs and kidneys; the remaining 90% is metabolized mainly by oxidative pathways in the liver and by nonoxidative pathways in extrahepatic tissues. Oxidative metabolism in the liver results in extensive displacement of the liver's normal metabolic substrates, the production of acetaldehyde and ROS, and an increase in the NADH/NAD⁺ ratio (Fig. 2).

Figure 2. Hepatitis C virus (HCV), alcohol metabolism, and liver damage. ALD, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; GSH, glutathione; HCC, hepatocellular carcinoma; IFN, interferon; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NADP, nicotinamide adenine dinucleotide phosphate; RNS, reactive nitrogen species; ROS, reactive oxygen species.

The major pathway of oxidative metabolism of ethanol in the liver involves multiple isoforms of cytosolic ADH, which results in the production of acetaldehyde. Accumulation of this highly reactive and toxic molecule contributes to liver damage. The oxidation of ethanol is accompanied by the reduction of NAD⁺ to NADH and, thereby, generates a highly reduced cytosolic environment in hepatocytes. The cytochrome P450 isozymes, including CYP2E1, 1A2, and 3A4, which are predominantly localized to the ER, also contribute to ethanol's oxidation to acetaldehyde in the liver. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing ethanol to acetaldehyde at elevated alcohol concentration. It also produces ROS, including hydroxyethyl, superoxide anion, and hydroxyl radicals.

Acetaldehyde, produced by ethanol oxidation, is rapidly metabolized mainly by mitochondrial ALDH2 to form acetate and NADH. Mitochondrial NADH is reoxidized by the electron transport chain (ETC). Most of the acetate resulting from ethanol metabolism escapes the liver to the blood and is eventually metabolized to CO₂ by way of the tricarboxylic acid cycle in tissues such as heart, skeletal muscle, and brain, where mitochondria are capable of converting acetate to the intermediate acetyl coenzyme A.

Consequences of alcohol metabolism by oxidative pathways

a) Acetaldehyde generation/adduct formation: if accumulated to high concentrations, acetaldehyde can form adducts with DNA and RNA, and decrease DNA repair. It also has the capacity to react with lysine residues on proteins including enzymes, microsomal proteins, microtubules, and affect their function. Formation of protein adducts in hepatocytes may contribute to impaired protein secretion, resulting in hepatomegaly. In addition, acetaldehyde and malondialdehyde (a by-product of lipid peroxidation) can combine and react with lysine residues on proteins, giving rise to stable malondialdehyde-acetaldehyde-protein adducts that are immunogenic and, thus, can contribute to immune-mediated liver damage.

b) Change in hepatocyte redox state (increase in NADH/NAD⁺ ratio): both acute and chronic alcohol consumption shift the redox state of the liver to a more reduced level, similar to but more pronounced than the shift observed in diabetes and during starvation. Alcohol metabolism produces a significant increase in the hepatic NADH/NAD⁺ ratio in both the cytosol and the mitochondria, as evidenced by an increase in the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, respectively, and vastly increases the availability of oxidizable NADH to the ETC in the mitochondria. The liver responds to ethanol exposure in part by increasing the rate of oxygen uptake, which may lead to periods of hypoxia, particularly in the downstream (pericentral) parts of the liver lobule.

c) Formation of ROS, reactive nitrogen species (RNS), and oxidative stress: Hepatic mitochondria produce ROS through the activity of the ETC as a by-product of oxidative phosphorylation. Normally, a small fraction of electrons entering the ETC can prematurely escape from complexes I and III and directly react with 1–3% of respiratory oxygen molecules to generate the superoxide anion radical, which is then dismutated by the mitochondrial manganese superoxide dismutase into hydrogen peroxide (H₂O₂). Mitochondrial glutathione peroxidase (GPx) then converts H₂O₂ into water by using reduced glutathione (GSH) as a cofactor. Thus, most of the ROS generated by the ETC in the normal state are detoxified by the mitochondrial antioxidant defenses. The nondetoxified portion of ROS diffuses out of mitochondria, and affects signal transduction pathways and gene expression, triggering cytokines, hormones, and growth factors, which if excessive may lead to hepatic inflammation, necrosis, and/or apoptosis. In addition, metals (e.g. iron and copper) can further react with H₂O₂ to produce hydroxyl radicals via the Fenton reaction (Fig. ).

Figure 3. Alcohol, reactive oxygen species (ROS), and mitochondrial dysfunction. CYP2E1, cytochrome P450 2E1; GSH, glutathione; GSSG, oxidized glutathione; H2O2, hydrogen peroxide; MnSOD, manganese superoxide dismutase; NO●, nitric oxide; O₂●^–, speroxide; ●OH, hydroxyl radical; ONOO^–, peroxinitrite.

Nitric oxide (NO), an RNS critical for hepatocyte biology, can interact with peroxides to generate peroxynitrite, which could be detrimental to the liver depending on the amount and duration. NO is produced by inducible nitric oxide synthase which is expressed in all liver cells (i.e. hepatocytes, stellate cells, Kupffer cells, and vascular endothelial cells) and its expression is induced by interleukin (IL)-1β alone or in combination with tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and/or lipopolysaccharide (LPS).

Ethanol-induced oxidative stress has been attributed to a decrease in the NAD⁺ : NADH ratio, acetaldehyde formation, CYP2E1 induction, hypoxia, cytokine signaling, mitochondrial damage, LPS activation of Kupffer cells, reduction in antioxidants particularly mitochondrial and cytosolic GSH, one electron oxidation of ethanol to 1-hydroxy ethyl radical, and the conversion of xanthine dehydrogenase to xanthine oxidase.

Fibrosis and cirrhosis

Fibrosis is a common response of the liver to a chronic inflammatory condition, where hepatic stellate cells (HSC) play a critical (though not exclusive) role.[19] HSCs exist in a quiescent state in the normal liver, but can be activated directly or indirectly in response to apoptotic or necrotic cell death. Cytokines released in the tissue as a result of injury further contribute to HSC activation, resulting in the expression of a myofibroblast phenotype and stimulating the expression of extracellular matrix (ECM) proteins, in particular collagen type 1, which are not normally expressed in the liver. Under conditions of an acute tissue injury, the deposition of collagen fibers is a transient wound-healing response and is followed by fibrinolysis mediated by metalloproteases that are activated as damaged tissue is replaced by newly generated liver cells by the regenerative response. Continuous tissue damage and repair after chronic inflammation, and an imbalance in the normal liver repair mechanisms results in excessive deposition of collagen fibers.[19]

Chronic ethanol consumption can influence this process at multiple levels: (i) enhancement of the pro-inflammatory environment in the liver by stimulating the release of pro-inflammatory cytokines from macrophages and decreasing the activity of protective cell types, including natural killer cells;[20] (ii) enhancement of hepatocyte apoptosis and necrosis in response to oxidative stress and shifting in stress defense signaling pathways; (iii) activation of HSCs and collagen formation (studies on isolated HSCs have demonstrated that ethanol alters their response to transforming growth factor (TGF-β) and IFN-γ through effects on intracellular signaling pathways); and (iv) suppression of the regenerative response to tissue damage that is an essential component of the liver's repair mechanism and thereby facilitates the deposition of scar tissue, which is the hallmark of fibrosis. This is probably accompanied by a suppression of metalloproteases (e.g. by the activation of inhibitor proteins, such as plasminogen activator inhibitor-1 [PAI-1]), which normally would maintain the balance of ECM deposition and resolution to facilitate tissue repair.[21]

Common factors involved in alcohol, obesity, and viral infection

Chronic heavy alcohol consumption, obesity, and viral infection have some common features/mechanisms that may contribute to exacerbation of liver damage when these conditions coexist. Several common mechanisms between two or more of these conditions have been advocated, including oxidative stress, CYP2E1 induction, increased fat synthesis and mobilization, selected gut bacteria, free fatty acids, ER stress, immune response, among others.[22-25] Because of page limitations, only the first two mechanisms (oxidative stress and CYP2E1 induction) will be discussed. Oxidative stress due to alcohol has been discussed earlier.

Obesity and oxidative stress

Obesity involves the accumulation of body fat and is a major risk factor for metabolic syndrome, which is characterized by hyperglycemia, dyslipidemia, and hypertension.[26] Increased oxidative stress in accumulated fat has been reported as a pathogenic mechanism of obesity-associated metabolic syndrome. In nondiabetic humans, systemic oxidative stress correlated positively with fat accumulation and negatively with plasma adiponectin levels. In obese mice, ROS production was selectively increased in adipose tissue, and was accompanied by enhanced expression of NADPH oxidase and decreased expression of anti-oxidative enzymes such as superoxide dismutase in white adipose tissue and GPx in liver.[27] In cultured adipocytes, mitochondrial and peroxisomal oxidation of fatty acids activates NADPH oxidase resulting in increased oxidative stress, which caused increase in messenger RNA (mRNA) expression of inflammatory (PAI-1, TNF-α, IL-6, and monocyte chemotactic protein-1), and suppression of mRNA and secretion of anti-inflammatory (adiponectin, leptin) adipocytokines. Conversely, in obese KKAy mice, treatment with apocynin, an NADPH oxidase inhibitor, reduced ROS production in adipose tissue, increased plasma adiponectin levels, and improved hyperlipidemia and hepatic steatosis. Because oxidative stress underlies the pathophysiology of hepatic steatosis,[28] these results suggest that increased oxidative stress in obese individuals could be further exacerbated by oxidative stress due to chronic heavy alcohol consumption.

Viral infection and oxidative stress

Infection with HCV, in most cases, develops into chronic disease which is manifested by steatosis and fibrosis, as well as HCC. HCV replication induces oxidative stress (Figure 2), which contributes to insulin and interferon resistance, as well as disorders of iron metabolism. Specifically, virus core and nonstructural NS5A proteins increase ROS levels through alteration of calcium homeostasis[29] via a primary effect on the uniporter,[30] and the induction of NADPH oxidase 4.[31] In addition, E1 and E2 and the transmembrane protein NS4B increase ROS generation via ER stress and unfolded protein response,[32, 33] and activates the antioxidant defense regulated by NF-E2-related factor 2.[34] Furthermore, HCV causes mitochondrial damage and induction of double-stranded DNA breaks mediated by NO and ROS, which is abolished by NO and ROS inhibitors.[35] HCV-induced ROS causes hepatic iron accumulation in mice by reducing hepcidin transcription, further magnifying ROS production,[36] and regulating TGF-β1.[37]

CYP2E1, alcohol, and oxidative stress

As mentioned earlier, alcohol-induced oxidative stress is a major mechanism by which ethanol causes liver injury. Of the many suggested pathways by which ethanol induces a state of oxidative stress, induction of CYP2E1 is a central one. Levels of CYP2E1 are increased after acute and chronic alcohol treatment. CYP2E1 generates ROS such as the superoxide anion radical and hydrogen peroxide and, in the presence of iron catalysts, produces the hydroxyl radical, a powerful oxidant (Figure 3). The role of CYP2E1 in chronic ethanol-induced liver injury was studied in wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Alcohol produced oxidant stress and steatosis in WT mice, but these effects were blunted in the KO mice and restored in the KI mice. These studies show that CYP2E1 contributes to ethanol-induced oxidant stress and liver injury.[38] For a discussion of the biochemical and toxicological properties of CYP2E1 and possible therapeutic implications for treatment of ALD by CYP2E1 inhibitors, the reader is referred to the review article by Lu and Cederbaum.[39]

CYP2E1, obesity, and oxidative stress

As discussed earlier, CYP2E1 is an important factor in liver disease. Several studies suggest that hepatic CYP2E1 activity is increased in patients with nonalcoholic steatohepatitis, chronic alcoholism, or morbid obesity. To study the correlation between obesity and CYP2E1, Emery et al.[40] assessed hepatic CYP2E1 activity—by determining the clearance of chlorzoxazone (CLZ), a CYP2E1-selective probe—in morbidly obese subjects with varying degrees of hepatic steatosis, and normal-weight controls. Obese subjects were evaluated at baseline and 1 year after gastroplasty, a procedure that leads to weight loss. Compared with controls, oral CLZ clearance was elevated approximately threefold in morbidly obese subjects, and was significantly higher among subjects with steatosis involving > 50% of hepatocytes. One year after gastroplasty, the median body mass index decreased by 33%, and total oral CLZ clearance declined by 46%. Thus, hepatic CYP2E1 activity is upregulated in morbidly obese subjects, and the positive association between the degree of steatosis and CYP2E1 activity preoperatively suggests that CYP2E1 induction is related to morbid obesity.[40] Similar results were obtained in genetically obese Zucker rats fed a normal diet (OB) when compared with normal Zucker rats fed a high-fat diet (HF). CYP2E1 induction was greater in both liver and fat of OB rats than in those of HF rats. The induction of CYP2E1 in liver and fat of obese patients may potentially alter the pharmacokinetics of lipophilic drugs metabolized by CYP2E1.[41]

In a recent study, Cederbaum reported that CYP2E1 induction potentiated liver injury in obese mice, and the elevated oxidative stress could be blunted by CYP2E1 inhibitors.[38] In addition, S-Adenosyl-L-methionine decreased oxidative stress, steatosis, liver injury, and mitochondrial dysfunction in the pyrazole-treated obese mice, an important finding with therapeutic implications in obesity-induced metabolic complications.

CYP2E1, HCV, and oxidative stress

CYP2E1 expression in the liver of patients with chronic hepatitis C correlated with the progression of hepatic disease (both lobular inflammation and fibrosis indices), and observed variations were consistent with the preferential distribution of CYP2E1 in the lobular zone.[42] The effect of alcohol metabolism on HCV replication and the antiviral action of IFN was studied in Huh-7 cells that harbor HCV replication and metabolize ethanol via the introduced expression of CYP2E1. Alcohol (up to 100 mmol/L) significantly increased HCV replication, which was dependent on CYP2E1 expression and alcohol-induced oxidative stress, and attenuated the anti-HCV action of IFN.[43] In chronic hepatitis C patients, cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.[44]

Alcohol's elevation of HCV titer in patients and increase of HCV RNA in replicon cells suggest that HCV replication is increased in the presence and absence of the complete viral replication cycle. Seronello et al.[45] used Huh7 human hepatoma cells that naturally express comparable levels of CYP2E1 as human liver to demonstrate that ethanol, at physiologically relevant concentrations, enhances complete HCV replication. Acetaldehyde, the first metabolite of ethanol, also enhanced HCV replication. They reported that elevated NADH/NAD⁺ is required for the potentiation of HCV replication by ethanol, and inhibiting CYP2E1 or ALDH suppressed replication. Thus, alteration of cellular NADH/NAD ratio is likely to play a critical role in the potentiation of HCV replication by ethanol (Fig. 4).

Figure 4. Summary of alcohol and HCV interactions. HCV, hepatitis C virus; IFN, interferon; ROS, reactive oxygen species.

Concluding remarks

Chronic heavy alcohol consumption in the presence of obesity and viral hepatitis could be damaging for the liver. While moderate alcohol consumption was associated with decreased prevalence of steatohepatitis in patients with NAFLD,[46] heavy alcohol consumption is discouraged whether an individual has NAFLD or not. The presence of common mechanisms for liver damage due to viruses, obesity, or chronic heavy alcohol consumption is relevant and may exacerbate damage to the liver when these three conditions exist. Further research is needed to clarify the interaction, if any, between moderate drinking, NAFLD, and viral hepatitis.

Conflict of interests

The author does not have any conflicting interests to declare.

References

Source

Brain Damage Caused by Drinking Alcohol Could Be Reversed by Aerobic Exercise

Dr. Douglas Fields

Neurobiologist and author, 'The Other Brain'

Posted: 09/04/2013 2:28 pm

There is no doubt that alcohol abuse causes brain damage and several other health problems, including cancer and liver disease. Some of the brain injury associated with alcohol abuse can be seen on a brain scan (MRI) as physical changes in brain structure and loss of brain tissue in wide-spread regions throughout the brain.

One of the most prominent changes associated with alcohol consumption involves the massive bundles of nerve fibers that interconnect neurons in different regions of the brain into functional circuits. These fibers are coated with a white-colored electrical insulation, called myelin, which is essential for transmission of electrical signals. These tracts of white matter streaking through the brain are the brain's information highways, and damage to them will impair any cognitive function that depends on information transmission through the communication cables. Loss of memory, slowed thinking, impaired problem solving and decision making are especially vulnerable to damage caused by alcohol consumption, because it disrupts white matter connections to the cerebral cortex and deep brain structures necessary for these mental functions.

Remarkably, a large body of new research has revealed that aerobic exercise not only builds muscle, it builds brain tissue. Aerobic exercise stimulates the birth of new neurons in specific parts of the brain where neurons can still divide in adults, including the hippocampus, which is involved in learning. Exercise protects against cognitive decline in aging and neurological diseases, including Alzheimer's, and it strengthens the integrity of white matter tracts to the extent that the beneficial changes can be seen on an MRI.

These recent discoveries motivated researchers Hollis Karoly and colleagues at the University of Colorado to ask whether aerobic exercise could prevent the damaging effects of heavy alcohol consumption on white matter in the human brain. Identifying any new treatment that could reverse brain damage caused by alcohol consumption would have profound health benefits for tens of thousands of individuals who consume alcohol. According to this new study, there is an effective treatment that requires no medication and has no negative side effects -- aerobic exercise.

To answer this intriguing hypothesis, the researchers compared the level of alcohol consumption in a population of men and women between the ages of 21-55 with the integrity of their white matter. This was accomplished by using an MRI brain imaging method that is highly sensitive to white matter integrity, called diffusion tensor imaging (DTI). Three conclusions were supported by the data, two of them confirming what was already shown in the literature, and the new finding reported here.

(1) White matter tracts in the brain are strongly affected by alcohol consumption. This was seen throughout the brain, but it was especially pronounced in some fiber tracts known to be necessary for higher level thinking and memory and other functions impaired in those who abuse alcohol. For example, the external capsule (EC) and superior longitudinal fasciculus (SLF) were especially sensitive to damage caused by drinking alcohol. When white matter integrity is graphed against the total number of alcoholic drinks consumed in 60 days (or other measures of alcohol consumption), white matter integrity drops in direct proportion to the amount of alcohol consumed.

(2) Conversely, white matter integrity increased in people who reported doing aerobic exercise in the last three months, and greater improvements were seen in those who did more than the average amount of exercise.

Both of these effects confirm and extend the result of other studies. The third result was that in people who exercised, the loss of white matter integrity caused by alcohol consumption was prevented or reduced, depending on how much exercise was done and which particular white matter tract in the brain is examined.

For example, in people who reported doing a moderate amount of aerobic exercise in the last three months (that is, the average amount of aerobic exercise among all participants), the integrity of the EC white matter tract was maintained even for the heaviest drinkers. Even better results in preserving white matter integrity were seen in subjects reporting an above average level of aerobic exercise. The steep, straight-line drop in white matter integrity plotted against the amount of alcohol consumption, leveled out completely in those participating in high levels of aerobic exercise; that is, no deleterious effects of alcohol consumption at any level of consumption could be seen in the white matter tracts of these people. Again, the magnitude of the effects differed somewhat in different white matter tracts, but in general the beneficial effects of exercise were evident throughout many white matter tracts in the brain.

The study also sorted the data according to self-reporting of cannabis use and tobacco smoking, because both of these have been implicated in white matter damage. Even accounting for these other effects on white matter structure, the beneficial effects of aerobic exercise on white matter integrity were still seen. The researchers conclude that the most damaging effects of alcohol consumption on white matter integrity are seen in those people who do not exercise regularly, "alcohol consumption did not appear to be associated with white matter damage among individuals who exercised regularly."

The design of this experiment can only provide correlative data. The associations revealed here must be tested in further experiments to show that there is a causal link between exercise and protection against white matter damage caused by drinking alcohol, and to uncover the biological mechanisms for the protection. However, these findings revealing the protective effects of aerobic exercise on preventing white matter brain damage in drinkers are compelling and valuable, regardless of whatever biological link to explain this correlation may be found in the future.

References:

All of the facts stated in this article are documented by citations to the scientific literature in the following paper reporting these new results:

Karoly, H.C., et al., (2013, in press) Aerobic exercise moderates the effect of heavy alcohol consumption on white matter damage. Alcoholism: Clinical and Experimental Research. Published on-line in advance of print.

For additional information on white matter see:

Fields, R.D. (2008) White Matter Matters, Scientific American, 298: 42-9.

Fields, R.D. (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 31: 361-70.

Source

Gene combinations help predict treatment success for alcoholism medication

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

For Immediate Release: Friday, August 2, 2013

NIH-funded study says five-marker genotype panel can guide ondansetron use

An experimental treatment for alcohol dependence works better in individuals who possess specific combinations of genes that regulate the function and binding of serotonin, a brain chemical affected by the treatment, according to a study supported by the National Institutes of Health. A report of the finding appears online in the American Journal of Psychiatry.

“This study is another important step toward personalized treatments for alcohol dependence,” says Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which funded the study. “A personalized approach based on a person’s genetic makeup is increasingly being investigated for delivering optimum treatment to the ‘right’ patient.”

Ondansetron is a medication currently used to treat nausea and vomiting, often following chemotherapy. It works by blocking serotonin-3 receptors, and has shown potential as a treatment for defined subpopulations with alcohol dependence.

In previous studies, Professor Bankole Johnson, D.Sc., M.D., and his team at the University of Virginia, Charlottesville, have shown that variations in genes that encode the serotonin transporter, a protein that regulates the concentration of serotonin between nerve cells, can significantly influence drinking intensity. They have also shown that the effectiveness of ondansetron therapy among people with alcohol dependence is influenced by variations of the serotonin transporter gene.

In the current study, Professor Johnson and his colleagues extended their prior work by analyzing variants of serotonin receptor genes, collectively designated as HTR3, among nearly 300 alcohol-dependent individuals who were participating in a clinical trial of ondansetron. They found that three HTR3 variants were significantly associated with the effectiveness of ondansetron treatment for alcohol dependence.

“Taken together, these studies implicate a collective effect of serotonin receptor and transporter gene combinations, defined by a five-marker genotype panel, on the response to treatment with ondansetron for a genetically defined subpopulation of individuals with alcohol dependence,” says Professor Johnson. “Multi-site, larger studies are about to begin to progress this work.”

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health^®

Reference

Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT3 antagonist ondansetron. Johnson, BA, et al. American Journal of Psychiatry. 2013 July 30. [Epub ahead of print]

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Alcohol consumption as a cofactor for other liver diseases†‡

Clinical Liver Disease

Special Issue: Alcoholic Liver Disease

Volume 2, Issue 2, pages 72–75, April 2013

Jose Altamirano^*, Javier Michelena

Article first published online: 24 APR 2013

DOI: 10.1002/cld.197

Copyright © 2013 the American Association for the Study of Liver Diseases

^† CIBERehd is funded by Instituto de Salud Carlos III. Javier Michelena received “Formación del Profesorado Universitaro” grant from the Ministerio de Educación of the Spanish Goverment.

^‡ Potential conflict of interest: Nothing to report.

Abstract

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Alcohol has been shown to cause synergistic injury in combination with other chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis B and C, hemochromatosis, and autoimmune liver diseases. Abusive alcohol consumption rapidly accelerates the development of hepatic fibrosis and cirrhosis and also increases the risk of liver cancer and death from liver disease. The negative impact of alcohol consumption is dose- and time-dependent and varies depending on the underlying liver disease and may occur at much lower alcohol intake compared with an alcohol dose necessary to initiate alcoholic liver disease itself. There is not a clear “safe” limit for alcohol consumption in the setting of chronic liver disease. Thus, alcohol consumption should be avoided or at least limited in any patient with underlying liver disease.

Abusive alcohol intake is a major risk factor for chronic liver disease (CLD). In addition, alcohol consumption in the presence of other liver diseases may result in progression of the disease. Alcoholic liver disease is prevalent among patients with chronic hepatitis C (HCV) and B (HBV) virus infection, influences the progression of the disease and has a stimulation effect on viral replication.1, 2 Alcohol may negatively impact the course of NAFLD increasing the fibrosis rate in patients with non-alcoholic steatohepatitis3 and of hereditary hemochromatosis (HH).4 Finally, alcohol may interact with the metabolism of certain drugs5 and can also contribute to the development and worsening of some autoimmune liver diseases.6

Alcohol and Chronic Hepatitis C

Chronic HCV infection is the leading cause of advanced liver disease in the United States; an estimated 3.2 million people have active chronic HCV infection.7 Alcohol consumption is a common comorbidity in these patients, and multiple studies have shown that it may result in synergistic injury, with accelerated rates of fibrosis and the development of cirrhosis and liver cancer.8–11 Various mechanisms have been proposed, including: alcohol's effect on HCV viral replication, HCV-related cytotoxicity, hepatic oxidative stress, and immune modulation.

There is evidence that HCV RNA levels increase in concert with a more pronounced alcohol intake (Fig. 1a).12 Conversely, it has been shown that serum HCV RNA decreases with a reduction in alcohol intake (Fig. 1b).2 Alcohol consumption is also associated with HCV progression, and there is extensive evidence showing that chronic alcohol consumption leads to disease progression (Table 1). Even small doses of alcohol intake (below 30 g/day) can promote liver fibrogenesis.13 Thus, it appears that there is no “safe alcohol consumption” among patients with HCV infection. Chronic alcohol consumption in HCV-infected patients stimulates not only fibrogenesis but also hepatocarcinogenesis. Patients with chronic HCV infection who actively consume alcohol have a higher relative risk of hepatocellular carcinoma (HCC) compared with abstainers (54 versus 19, respectively).14 This risk also appears to be dose-dependent. In one study, alcohol consumption >80 g/day increased the risk for HCC significantly by a factor of 7.3 when compared with <40 g/day.11 Finally, there are data showing that alcoholics have inferior rates of response to HCV therapy.15 However, the question about a possible inhibitory effect of alcohol on therapy rather than patient noncompliance requires further research.

Figure 1. Impact of alcohol consumption and effect of alcohol reduction on serum HCV RNA levels. Abbreviations: HCV, hepatitis C virus; SRAC, self-reported alcohol consumption. (a) Adapted with permission from Hepatology.12 Copyright 1998, Wiley. (b) Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Table 1. Effect of Alcohol Consumption in the Progression of HCV Infection

Study	Alcohol Intake Evaluation	No. of Patients	Results
Roudot-Thoraval et al.33	Excessive alcohol intake defined as >5 drinks/day for women and 6 drinks/day for men for >1 year	6,664	Excessive alcohol intake was also associated with a higher risk of cirrhosis (34.9% versus 18.2%; P < 0.001).
Poynard et al.34	Abstinent/Moderate, <50 g/day; high, ≥50 g/day	2,235	Fibrosis rate progression increased from 0.125 to 0.167 in patients with consumption ≥50 g/day
Pessione et al.12	Weekly self-reported alcohol consumption	233	Significant correlation between self-reported alcohol consumption and serum HCV RNA levels (r = 0.26; P = 0.001)
Corrao et al.35	Lifetime daily alcohol intake	702	Alcohol intake + HCV infection multiplies the alcohol-associated risk of cirrhosis (odds ratio: 9.0 for 50 g/day, 26.1 for 100 g/day, 133 for >125 g/day)
Harris et al.36	Heavy drinking defined as >80 g/day	836	Heavy drinking exacerbates the risk for cirrhosis among patients with HCV infection (odds ratio: 7.8 versus 31.1 in HCV and HCV heavy drinkers, respectively)

Alcohol and Chronic Hepatitis B

The interaction of alcohol consumption with HBV infection has been studied less extensively. Alcohol stimulates carcinogenesis in patients with HBV. This effect was shown in the seminal study of Ohnishi et al.,16 in which patients with HBV infection and active alcohol consumption developed HCC approximately 10 years earlier than patients who did not drink at all. Additionally, a dose-dependent effect of alcohol consumption has been demonstrated. Patients with heavy alcohol consumption (>80g/day) had a significantly increased risk of HCC in HBV-related cirrhosis.17

Alcohol and NAFLD

NAFLD is increasingly recognized as the downstream hepatic consequence of the metabolic syndrome. Well-known risk factors for NAFLD include obesity (especially with increased waist circumference), insulin resistance, and hypertriglyceridemia. Small amounts of alcohol may improve peripheral insulin resistance that take place in NAFLD.18 In addition, some studies have shown a paradoxical association between modest alcohol consumption with a lesser degree of severity in NAFLD patients.19, 20 However, additional alcohol consumption worsens NAFLD at various stages of the disease, both in animals5 and in humans.21–23

There is evidence that the impact of alcohol consumption on the development of NALFD is dose-dependent. Studies from Europe have shown that alcohol consumption of more than 60 g/day increases the rate of fatty liver by echography to 46% compared with 16% in control subjects.24 Alcohol consumption has also shown an additive risk for NAFLD development in obese patients. In one study, individuals with a body mass index of more than 25 kg/m² had a further increase in fatty liver to >70%, and if both alcohol consumption and overweight were factors, steatosis was present in >90%.22

On the other hand, liver fibrosis in NAFLD also increases with alcohol consumption. Patients with high-risk alcohol consumption and obesity have an almost two-fold risk of developing cirrhosis21 (Fig. 2).

Figure 2. Obesity is a risk factor for alcoholic liver disease progression. Abbreviation: BMI, body mass index. Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.

Finally, recent evidence shows that even social drinking in patients with nonalcoholic steatohepatitis results in a significantly increased risk of HCC.25 This observation is in keeping with animal studies showing that alcohol administration is associated with deterioration of experimentally induced fatty liver disease in rodents and may also enhance the generation of carcinogenic DNA lesions.26

Alcohol Consumption and Hereditary Hemochromatosis

HH is an autosomal recessive gene disorder in which HFE gene mutations cause chronic intestinal hyperabsorption of iron, resulting in iron overload in various organs.27, 28 Iron overload is a negative prognostic factor for the development of liver disease.4 Alcohol consumption increases reactive oxygen species by producing H₂O₂, which leads to iron hyperabsorption and iron release due to a decrease in hepcidin. This leads to iron accumulation in the liver, resulting in increased toxicity (Fig. 3). One observational study showed that hemochromatosis subjects who drank >60 g/day of alcohol were approximately nine times more likely to develop cirrhosis than those who drank <60 g/day.29 Thus, patients diagnosed with HH should avoid alcohol consumption.

Figure 3. Iron overload due to alcoholic liver disease. Abbreviations: EtOH, ethanol; ROS, reactive oxygen species; TfR1, transferrin receptor 1.

Alcohol, Drug Interactions and Autoimmune Liver Diseases

Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially well known for methotrexate, paracetamol, and antituberculosis drugs. First, prolonged high-dose methotrexate intake results in stellate cell activation leading to zone 3 fibrosis, which is further enhanced by alcohol consumption, since alcohol by itself leads to an activation of stellate cells.30 Second, alcohol consumption induces cytochrome P450 2E, which is also responsible for the metabolism of various drugs (e.g., paracetamol and antituberculosis drugs such as isoniazid). An induction of CYP2E1 by alcohol results in enhanced metabolism of paracetamol with an increased generation of highly toxic intermediates that are not normally detoxified due to the decreased hepatic glutathione levels presented in alcoholic patients. Isoniazid toxicity depends on two factors: (1) the speed of isoniazid acetylation and (2) the speed of the metabolism of the intermediate acetylhydrazine by CYP2E1.31 Finally, it should be pointed out that vitamin A and beta-carotene taken in excess may also lead to hepatic fibrosis and cirrhosis.

The effect of alcohol consumption in patients with autoimmune liver diseases has not been studied extensively, though there is some clinical evidence in patients with primary biliary cirrhosis (PBC). In a study of 274 patients with untreated PBC, moderate alcohol consumption (30 g/day) was an independent predictor of advanced PBC stage.32 In these patients, moderate alcohol consumption was also significantly correlated with increased oxidative stress and steatosis on liver biopsies, which was thought to contribute to worsening of PBC stage.

Summary

Alcohol has been shown to cause synergistic injury in combination with other forms of CLD, particularly chronic HCV and HBV infection, NAFLD, HH, and autoimmune liver disease. Alcohol consumption, particularly in high doses, accelerates to liver fibrogenesis and the development of cirrhosis and also increases the risk of HCC and death from liver disease. Despite the effect of light alcohol consumption on decreasing insulin resistance and cardiovascular mortality, there does not seem to be a “safe” limit for alcohol consumption in the setting of combined CLD.

References

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