Sex Differences in Alcohol Consumption and Alcohol-Associated Liver Disease

Alcohol-associated liver disease is becoming increasingly prevalent.

Alcohol-associated liver disease affects men more often than women, but they differences between the sexes is narrowing. 

Women develop liver disease with lesser alcohol exposure and suffer worse disease as compared with men. 

Women who represent a rapidly growing subset of patients with alcohol-associated liver disease.

Alcohol-related liver disease is second to nonalcoholic fatty liver disease as the leading cause of cirrhosis in the United States.

There is a lifetime prevalence of severe alcohol use disorder in the United States in 18.3% of men and 9.7% of women.

Men have significantly higher rates of alcohol consumption and high-volume drinking in comparison to women, consistently surpass women in drinking frequency, quantity, and rate of binge drinking.

The above pattern occurs throughout the world and across different cultures. 

Women who previously consumed large amounts of alcohol are more likely to quit drinking than their male counterparts. 

Overall mortality from alcoholic liver disease in the United States has increased in almost every age group and race, with the exception of non-Hispanic black men.

A systematic review and meta-analysis of more than 2 million patients found that consumption of one to two drinks per day as compared with long-term alcohol abstinence was associated with an increased risk of liver cirrhosis in women, but not in men. 

The  risk for the development of cirrhosis is consistently higher in women than in men for all levels of alcohol consumption.

Younger patients admitted with alcohol-associated liver disease with acute-on-chronic liver failure were more likely to be women, Hispanic, and obese.

The United Kingdom Million Women Study evaluated alcohol consumption with meals, daily use of alcohol, and liver cirrhosis in more than 400,000 women without history of cirrhosis or hepatitis: women who consumed alcohol with meals had a relative risk (RR) of 0.69 for cirrhosis development compared with those who typically did not consume their alcohol with meals, after adjustment for amount consumed. 

Daily alcohol consumption in addition to not consuming alcohol with meals was associated with more than a doubling of cirrhosis incidence.

The threshold amount of alcohol that results in alcoholic liver disease in women is half that of men.

Women may have increased liver disease progression despite sobriety in comparison to men.

Women represent a growing subset of the alcohol-associated liver disease patient population; and sex differences in trends in alcohol consumption and disease development and progression are important aspects of understanding the worse trajectory women tend to have as compared with men.

Obesity is a known risk factor for the development and progression of alcohol-associated liver injury.

The duration of alcohol use, and being overweight or obese are risk factors for alcohol-associated liver disease: age, female sex, and duration of alcohol use were independently correlated with cirrhosis. 

 Rising female consumption and overweight were independent risk factors for the development of acute alcoholic hepatitis. 

Being overweight for 10 years or more was an independent risk factor for cirrhosis, acute alcoholic hepatitis, and steatosis.

A cohort study of more than 1 million patients in the United Kingdom found that as BMI increased above 25 kg/m2, the incidence of cirrhosis increased. 

Approximately 17% of liver cirrhosis was found to be attributable to excess body weight and 42% was attributable to alcohol.

Medications used for minimizing cravings for substances of abuse, such as naltrexone and bupropion, have been associated with reduced BMI in weight loss studies, and have an additional benefit aside from sobriety assistance in promoting weight loss and liver disease risk reduction in overweight and obese patients with alcohol-associated liver disease. 

In  female patients 28% of participants with gastric bypass endorsed problems with alcohol control after surgery in comparison to only 5% who endorsed problems with alcohol control before surgery.

A gastric bypass surgery group drank significantly more alcoholic beverages per day after their surgery as compared with before their surgery.

It is  likely neurohormonal consequences of gastric resection contribute to alcohol use. 

Alterations in ghrelin signaling as a consequence of surgical resection may contribute to changes in alcohol intake after gastric bypass surgery. 

There may also be a neurobehavioral component of the reward pathway that is altered by gastric bypass surgery.

The development of alcohol use disorder after bariatric surgery is often delayed, occurring many months or years after surgery.

Alcohol consumption is affected by gastric bypass surgery, and alcohol metabolism is altered as well. 

A gastric bypass group has a significantly higher peak alcohol breath level and requires greater time to return to zero on breath alcohol testing in comparison to normal weighted controls.

Bariatric surgery is far more common in women than in men, and this may be an additional risk factor contributing to sex differences in the development and progression of alcohol-associated liver disease.

Studies demonstrated that men are more likely to consume alcohol and are more likely to binge drink as compared with women, but this gender gap is narrowing.

As the number of women in the workforce continues to increase and women attain increasing educational and occupational opportunities, these may contribute to normalization of alcohol consumption and increased high-risk drinking.

While  men have more substance use disorders than women, there is a significant narrowing of the difference between men and women. 

The mean frequencies of men’s and women’s drinking in both public and private settings across various countries are highly correlated, indicating that there are non–sex related factors that contribute to drinking behavior. 

Alcohol consumption in the public and private settings are two different entities.

Women are more commonly affected by alcohol-induced liver injury.

The liver is the primary organ of alcohol metabolism and as such is the main site of injury in patients with excessive alcohol consumption. 

 Alcohol-associated liver diseases include: alcoholic hepatitis, alcoholic steatosis, alcoholic steatohepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma.

In Denmark, in people who consumed 28 to 41 alcoholic drinks per week, women had an RR of 17.0 for alcohol-induced cirrhosis compared to an RR of 7.0 in men. 

At any given level of alcohol intake, women had a higher relative risk of developing alcohol-induced liver disease and alcohol-induced cirrhosis compared with men.

Women have a significantly more rapid progression to cirrhosis from alcohol:20 years on average, as compared with the rate of progression to cirrhosis in men 35 years on average.

In a trial of 490,000 men and women who reported their alcohol and tobacco use, mortality from alcohol-associated disease as a whole was not significantly different between men and women for those consuming two to three drinks per day. 

Mortality did increase in men who consumed four or more drinks per day.

Gender is not predictive of survival in acute liver failure.

Serum alcohol levels are determined by the rate of alcohol absorption from the gastrointestinal (GI) tract, the volume of distribution in the body, and the rate of elimination.

Alcohol is absorbed throughout the GI tract, the majority of which occurs in the small intestine. 

Following absorption it travels to the liver and then is distributed throughout the body water.

First-pass metabolism of alcohol occurs through the liver, which serves as the primary metabolizer.

Alcohol is eliminated from the body primarily through oxidation via the enzyme alcohol dehydrogenase (ADH).

Alcohol dehydrogenase (ADH) enzymes are located throughout the GI tract and the liver as well as in other tissues including adipose, breast, brain, and whole blood.

Alcohol-related liver injury is caused by ethanol metabolism by alcohol dehydrogenase and cytochrome P450 pathways that produce the hepatotoxin acetaldehyde.

Sex differences in the pharmacokinetics of alcohol: women develop higher blood alcohol levels when compared with men.

Females are generally smaller than males; therefore, the same alcohol consumption results in higher serum alcohol levels in females as compared with males.

Females have smaller body water content per kilogram of body weight when compared with males leading to a smaller volume of distribution.

Women have decreased gastric ADH

Women have slower gastric emptying of alcohol and  increased bioavailability of alcohol.

There is a difference between gastric alcohol dehydrogenase (ADH) activities in women versus men. 

The metabolism of alcohol by gastric ADH decreases its systemic bioavailability. 

The stomach protects against systemic absorption of alcohol via ADH activity.

Alcoholic and nonalcoholic women had significantly higher blood alcohol concentrations compared with their male counterparts when the alcohol was ingested; but no significant difference between the sexes when the alcohol was administered intravenously. 

Nonalcoholic men had 70% to 80% higher gastric alcohol dehydrogenase  activity compared with nonalcoholic women. 

Chronic alcohol abuse reduced gastric ADH by 37% to 46% in men as compared with only an 11% to 20% reduction in women. 

Women have increased bioavailability of alcohol due to decreased first-pass metabolism, leading to increased susceptibility to liver disease.

Decreased gastric metabolism in females due to significantly less active gastric ADH is the primary reason for sex differences in serum alcohol levels.

Sex differences in gastric ADH activity are amplified in patients who have undergone gastric bypass surgery, wherein gastric alcohol dehydrogenase is circumvented, contributing to an increased risk of alcohol-associated liver disease related to first-pass metabolism.

Chronic alcohol intake alters hormone expression in both sexes. 

Estrogen modulates liver activity through estrogen receptors on hepatic cells. 

With chronic alcohol consumption postmenopausal women have  approximately two-fold higher estrogen levels.

Estrogen stimulates growth hormone secretion.

Growth hormone increases hepatic ADH activity.

It is hypothesized that increased hepatic ADH activity in females leads to increased accumulation of toxic acetaldehyde and that this contributes to the increased susceptibility of females to alcohol-related liver disease

Excessive alcohol consumption disrupts the GI barrier and promotes bacterial translocation from the GI lumen into the portal vein.

Endotoxin is a lipopolysaccharide, and is a part of the outer wall of gram-negative bacteria. 

Kupffer cells are macrophages localized to the liver, and one of its functions is to remove endotoxin, which results in Kupffer cell activation and cytokine secretion.

Kupffer cells produce proinflammatory cytokines and reactive oxygen species.

Abstinence from alcohol is the cornerstone of therapy in both men and women. 

Only 15% of people who have had alcohol use disorder at some point in their lives seek treatment, and only 28% of people who have had both alcohol use disorder and dependence report having sought treatment.

There is a relatively low proportion of female participants in substance abuse treatment programs.

Female drinkers at-risk for alcohol use disorder are  more likely than men to have a lifetime history of sexual and physical abuse.

Approximately one-third of AA members are women.

Stigma behind women consuming alcohol that has downstream repercussions including lack of insight into recognizing oneself as having alcohol use disorder and therefore less incentive to seek care.

Medications used for alcohol cessation include naltrexone, acamprosate, baclofen, and disulfiram. 

Baclofen dose for alcohol craving reduction in women was significantly lower than that in men to achieve craving control, as the amount of daily alcohol consumption was also significantly less in women as compared with men.

Women benefit from naltrexone and/or behavioral therapy in the context of medical management with similar benefit to their male counterparts.

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