November 19, 2020

Exploring the Role of Sex and Gender Differences in Liver Health

woman holding drawing of sad liver

By Shivani Chinnappan, SWHR Programs Coordinator

This post is part of SWHR’s blog series to raise awareness about liver health issues that impact women. Read our previous blog on primary biliary cholangitis (PBC), a rare autoimmune liver disease that overwhelmingly affects women.

The liver performs hundreds of functions vital to our health, including processing food, medicine, alcohol, and other toxins. Research shows that clear differences in liver health and disease exist between women and men.

The study of sex and gender differences in the prevention, presentation, diagnosis, and treatment of diseases is critical to improving health outcomes for all, and liver diseases are no exception. “Gender differences in incidence, presentation, natural history, and outcomes exist for common liver diseases,” according to a 2013 review article in Gastroenterology & Hepatology. However, the biological pathways behind many of these differences are still largely unknown and need to be studied.

Autoimmune Liver Disorders

When people think of liver health, many only consider diseases caused by consumption of alcohol. But some liver conditions are not caused by alcohol, such as autoimmune liver disorders (though alcohol consumption may exacerbate these liver diseases).

Autoimmune diseases generally are much more common in women than men, including ones that affect the liver. For example, women are 9 times more likely to be diagnosed with primary biliary cholangitis and 4 times more likely to be diagnosed with autoimmune hepatitis, both liver diseases thought to occur when the body’s immune system attacks healthy liver cells.

Although researchers don’t know the exact reasons behind this disparity in the prevalence of autoimmune liver diseases, sex hormones are thought to play a role, as they can influence gene expression and dictate the function of immune response receptors.

Liver Tumors

Liver tumor presentation also differs between women and men, with benign tumors more common in women and malignant tumors more common in men.

For instance, a rare benign tumor called hepatocellular adenoma occurs mostly in reproductive-age women and is associated with use of oral contraceptives. One study showed significant reduction in tumor growth with the cessation of oral contraceptive pills, leading researchers to believe sex hormones play a pivotal role in the development of these tumors.

Meanwhile, hepatocellular carcinoma (HCC), the most common form of liver cancer, occurs more frequently in men. “This gender bias has been attributed to female sex hormones, as HCC incidence markedly increases in postmenopausal women who do not take hormone replacement therapy,” according to a report in Nature Reviews Cancer. Research in zebrafish found that androgen accelerates tumor progression in females while estrogen attenuates liver tumors in males. While studies suggest hormones are involved in tumor development, more research is needed to determine the exact mechanisms behind this sexual dimorphism.

Alcohol and Toxin Liver Issues

Alcohol affects women’s bodies differently than men’s bodies — and not just because women typically weigh less than men. For example, women generally have less water in their bodies than men, causing the proportional level of alcohol in the blood to be higher. They also produce a smaller amount of alcohol dehydrogenase, a liver enzyme that breaks down alcohol in the bloodstream, leaving women’s bodies more susceptible to the damaging effects of alcohol.

So while men are more likely to experience alcoholic liver disease due to higher rates of alcohol use disorder, women with alcoholic liver disease show more rapid progression to fibrosis, a buildup of scar tissue in the organ. Fibrosis can lead to serious long-term liver issues, such as cirrhosis, in which severe scarring results in poor liver function.

Women are also drinking more than before, increasing concerns about alcohol-related liver diseases. A 2017 report showed a nearly 84% jump in alcohol use disorders among women from 2001-2012, compared to a 35% increase for men. During the COVID-19 pandemic, a national survey found significant increases in heavy drinking and alcohol-related problems for women. Another study showed a 50% increase in alcohol-related cirrhosis in women from 2009-2015, compared to a 30% increase in men.

In addition, women are more susceptible to drug-induced liver injury and acute liver failure. In one study, women accounted for more than 70% of patients hospitalized with acute liver injury due to acetaminophen and unintended drug reactions. Researchers theorize the female preponderance of drug-induced liver injury may be related to sex-based differences in the expression of genes that affect liver metabolic function and pathophysiology.

Liver Transplants

Women are 20% less likely to receive liver transplants than men. “More than a decade of research shows that women in the United States with cirrhosis are less likely to receive a liver transplant, and more likely to die on the waitlist, than men,” according to an article in Gastroenterology & Endoscopy News.

The Model for End-Stage Liver Disease (MELD) is a formula that looks at several factors to produce a score that dictates a patient’s priority level on the organ transplant list. But there are certain biological differences that may put women at a disadvantage from this scoring system.

For example, men typically have higher muscle mass, resulting in naturally higher levels of creatinine, a chemical byproduct commonly used to measure renal function. Creatinine levels affect overall MELD score, giving men an advantage.

Men are also more susceptible to malignant liver cancers, which bumps their MELD scores up, while women are more susceptible to autoimmune and inflammatory diseases, which have no exception built into the system to receive transplants sooner.

There are also fewer smaller-sized livers available for transplant into smaller female patients, as men are more likely to engage in risky behaviors that lead to the donation of organs. In addition, restrictions on geographic allocation of livers make it even more complicated for women to access already-scarce liver transplant options. Systematic review of transplant policy and procedure could help close this gap in female liver health and bring much-needed transplants to a disadvantaged health population.

Further Need in Liver Sex Difference Research

A better understanding of how sex and gender differences affect liver health and disease is vital to achieving individualized health care and informed decision-making for all patients. Although gaps have been identified in women’s liver health, there is much more work to do to find mechanisms and solutions that could ameliorate these disparities. Continued research is needed on the different ways that sex and gender may influence the presentation, prevention, diagnosis, and treatment of liver diseases in order to bring us another step closer to keeping women healthy.

SWHR’s blog series on women’s liver health is supported by a grant from Intercept Pharmaceuticals Inc. SWHR maintains editorial control and independence over blog content.