Rite of Passage or Road to Early Liver Damage?

As a transplant hepatologist in Los Angeles, Brian Lee, MD, MAS, has seen his share of alcoholics with advanced liver disease, people who have spent decades drinking their body toward an early death.

In recent years, however, the demographic of these patients has shifted in a particularly worrisome direction. More than ever, young adults and even late adolescents too young to drink legally are showing signs of organ damage after just a few years of problem alcohol use.

“I’ve been seeing a lot of 20-year-olds with end-stage liver disease and liver failure,” said Lee, an associate professor of medicine at the Keck School of Medicine of USC, Los Angeles. “Young adults with alcohol-associated liver disease [ALD] are the fastest growing demographic contributing to liver-related mortality.”

However, because ALD may not cause any symptoms until cirrhosis develops, and young adults may not divulge the full extent of their drinking, primary care providers should actively screen for alcohol use and organ damage in young adults before they wind up on the liver transplant list.

Between 2013 and 2018, the number of people younger than 40 years on the liver transplant list with a diagnosis of ALD quadrupled, from 3 per 100,000 to 13 per 100,000, making the condition the most common indication for a liver transplant in this age group.

A review of death certificates in the 3 years prior to the pandemic also showed a steady rise in deaths from ALD in young adults. But mortality rates accelerated in 2020, with some of the biggest increases seen in those aged 25-34 years; deaths among men and women in that age group saw increases of 51% and 38%, respectively.

Not surprisingly, growing alcohol use during the pandemic was well-documented. Lee reviewed retail sales data in the United States between April and June of 2020 and showed a 34% increase in sales of alcohol, from $7.10 billion to $9.55 billion, compared with 2019. The largest increases occurred among people younger than 44 years.

After the lockdowns had ended, Lee and his colleagues were curious to see if drinking patterns changed. Using the National Health Interview Survey from 2018 to 2022, they found alcohol consumption remained elevated in 2022, with adults aged 18-39 years and 40-49 years most likely to report any drinking in the past year.

But the biggest increases over the 4 years were among people aged 18-39 years, with 73.3% reporting any alcohol use in 2022 compared with 70.2% in 2018. An even bigger concern, however, is the prevalence of dangerous drinking: The 2023 National Survey on Drug Use and Health found that 28.7% of adults aged 18-25 years reported binge drinking in the past month, and 10.9% met the criteria for alcoholic use disorder.

Twin Epidemics: Not Just Alcohol

Alcohol is not the only factor driving the rise in liver disease in young adults. Lee also linked the jump to the obesity epidemic.

Trends identified by the National Health and Nutrition Examination Survey are striking. The 1976-1980 survey found that the prevalence of obesity in persons aged 18-25 years was 5.5%. By the 2017-2018 survey, the prevalence rose to 32.6%.

That increase is helping drive the increases in liver transplants and ALD-related deaths. “There’s an interaction between metabolic risk factors, particularly obesity and diabetes, and increased alcohol consumption,” Lee said. “They’re not just additive in terms of developing liver fibrosis or liver failure; they’re really multiplicative.”

Non–alcoholic fatty liver disease, recently renamed metabolic dysfunction–associated steatotic liver disease (MASLD), is the most common cause of chronic liver disease worldwide. Ashwani Singal, MD, MS, a professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at the University of Louisville School of Medicine in Louisville, Kentucky, served as a panelist on the consensus panel that came up with the name change. Given the stigma associated with the terms “fatty” and “alcoholic,” the group proposed the use of the overarching term “steatotic liver disease” (SLD) to describe conditions involving fat accumulation in the liver.

Singal spoke with Medscape Medical News about the changes in nomenclature and the different subsets of SLD. The presence of one of five cardiometabolic risk factors — obesity, hypertension, diabetes, low high-density lipoprotein cholesterol, or high triglycerides — in a patient found to have steatosis by imaging such as liver elastography (FibroScan) indicates the presence of SLD, which has further subdivisions depending on alcohol intake.

“Depending on alcohol consumption, based on below 20 grams per day for women and 30 grams per day for men, or 60 grams per day for men and 50 grams per day for women, individuals are categorized as MASLD or ALD. If alcohol intake is between these cutoffs, they are classified as metabolic dysfunction–associated ALD,” Singal said. This scoring is based on 14 g of alcohol in the United States and 10 g according to the World Health Organization, as the equivalent of one drink.

These distinctions matter because the risk for progression to cirrhosis and choice of treatment vary by subtype. For patients with advanced fibrosis, the 5-year risk of developing decompensated cirrhosis rises dramatically with increasing alcohol use. For MASLD, metabolic dysfunction–associated ALD, and ALD, the risks are 5%-15%, 10%-30%, and 15%-50%, respectively.

Not only does alcohol independently damage the liver, but it also contributes to the metabolic issues at the root of SLD. “If somebody is drinking five drinks a day, each drink has about 100 calories. Those are all empty calories, right?” said Singal, describing the link between alcohol and obesity. He also pointed out that alcohol can worsen hypertension and dyslipidemia, two of the other risk factors for SLD.

Listening for Signs of a Silent Disease

SLD is a silent disease, and patients are most often detected due to abnormal liver chemistries or a finding of steatosis in the liver from an ultrasound performed for another indication. This lack of definitive symptoms raises the question about the most efficient strategy to screen for SLD.

The prevalence of the condition is > 70% in patients with type 2 diabetes, and > 90% of patients with SLD have one of the five cardiometabolic risk factors. Practice guidelines for MASLD from the American Association for the Study of Liver Diseases recommend noninvasive screening for any patient with one of the five key cardiometabolic risk factors, imaging findings of hepatic steatosis, unexplained abnormal levels of alanine aminotransferase or aspartate aminotransferase, a family history of cirrhosis, or heavy consumption of alcohol.

“The most common referral to a hepatologist is because of elevated liver enzymes,” Lee said. “But many patients with advanced liver fibrosis won’t have abnormal liver enzymes.” He recommends primary care clinicians start by obtaining a fibrosis-4 (FIB-4) score, which is calculated based on the patient’s age, platelet count, and liver enzymes. If the result is > 2.67, he recommends referral to gastroenterology or hepatology.

Although the FIB-4 has both high sensitivity and negative predictive value, its rate of false positivity also is high. If the FIB-4 result is borderline — between 1.3 and 2.67 — Singal recommended a more specific test such as the enhanced liver fibrosis (ELF) score, which has a much higher positive predictive value. An ELF score > 7.7 indicates the need for the services of a gastroenterologist or hepatologist.

A drawback of the ELF score, which is based on levels of hyaluronic acid, tissue inhibitor of metalloproteinase-1, and procollagen III N-terminal peptide, is specimens will likely need to be shipped to a reference lab. The relatively simpler FIB-4 remains the initial choice for primary care settings.

For patients who do not meet these criteria for referral, primary care clinicians should repeat the FIB-4 every 1-2 years for patients with type 2 or pre-type 2 diabetes or two or more other risk factors. If the patient does not have type 2 diabetes and has only one of the five cardiometabolic risk factors, the FIB-4 can be done every 2-3 years according to the guidelines.

Since the required lab values for calculation of the FIB-4 are commonly performed in primary care settings, the electronic health record (EHR) can be leveraged to streamline workflows in identifying patients at risk for SLD. A prospective study performed in a university general medicine practice that focused on identifying patients with diabetes with abnormal FIB-4 levels found that 86% of patients with diabetes referred to specialists received a diagnosis of MASLD, of whom 36% were found to have advanced fibrosis.

Best Practices for Alcohol Screening

Although many primary care physicians ask new patients about alcohol use, only a minority use formal alcohol screening tools.

But, just as with many other health screenings, leveraging the EHR can ease the burden. A quality improvement study in six urban primary care clinics evaluated the use of a — validated screening test, the three-item Alcohol Use Disorders Identification Test–Consumption items. For patients flagged by the EHR with moderate- to high-risk alcohol use (defined by standard cutoffs for moderate-risk use of alcohol), clinicians could take advantage of a brief counseling script also built into the clinical decision support tool.

“We achieved very high screening rates, with an overall screening rate of over 70% in the first year, whereas in most practices that haven’t made a concerted effort, it’s less than 10%,” said Jennifer McNeely, MD, a professor in the Departments of both Medicine and Population Health at the New York University Grossman School of Medicine, New York City, who led the research. McNeely discovered some additional factors that improved the identification of patients at risk.

“Don’t limit use of the screening tool to preventive care visits because the clinics that used that had 20%-40% screening rates versus over 90% screening rates for the ones that used any routine visit,” she said. She also found that the use of a self-administered questionnaire is better at detecting risky alcohol use: The clinic that trained medical assistants to ask the questions identified moderate- to high-risk drinking in only 1.6% of its patients compared with rates of 14.7%-36.6% in the remaining facilities.

The counseling script was used infrequently by the various clinics, with rates ranging from 0.1% to 12.5%. McNeely acknowledged that primary care providers are already overstretched and that counseling about alcohol and drug use is more difficult than many health issues. But she said clinicians are credible messengers for young people, perhaps more so than teachers or parents, and expressing concern about a patient’s health is often a good starting point.

Primary care clinicians also should become more comfortable with pharmaceutical approaches to help patients reduce drinking and maintain abstinence, she said.

“There are effective medications that are totally underutilized,” McNeely said. According to a review by the Agency for Healthcare Research and Quality, oral naltrexone, acamprosate, and topiramate have the strongest evidence for reducing alcohol consumption in outpatient settings.

Most importantly, McNeely encouraged clinicians not to ignore unhealthy levels of alcohol use, because doing so can send the wrong message. “Oftentimes providers don’t know what to say, so they say nothing,” she said. “That can be a tacit endorsement.”

Lee, Singal, and McNeely reported no financial conflicts of interest. 

A former pediatrician and disease detective, Ann Thomas, MD, MPH, is a freelance science writer living in Portland, Oregon.