Decoding the silent epidemic of liver disease

The liver, the largest organ in the body, is a workhorse. It carries out hundreds of essential tasks everyday, including digesting your food, cleaning your blood, and making essential proteins. But when things with the liver begin to go awry, its owner often isn’t aware.

Liver disease is a major — and often underappreciated — public health issue. In general, liver conditions are associated with metabolic conditions writ large, and so are only set to increase as rates of obesity and diabetes among the general population also mushroom. An estimated 4.5 million adults in the United States have liver disease; that’s 1.5% of the population, and liver disease results in around 57,000 deaths a year. Those from marginalized socioeconomic backgrounds tend to fare worse: A paper published in late 2024 found that certain groups are more affected than others. In particular, Hispanic adults showed a higher prevalence of a certain type of liver disease than other racial and ethnic groups, potentially due in part to a genetic predisposition, as well as higher rates of diabetes and obesity in this population. The authors pointed out that cases may be going undiagnosed and called for better ways of detecting the disease earlier, because catching the condition too late increases the chance of complications such as liver cancer, liver failure, and the need for a transplant.

Among those who have liver disease, another subset will develop progressive liver disease. That number is also set to rise: “End-stage liver disease is forecasted to increase over the next decade — a burden on not only the patient who suffers a poorer quality of life, but also on their loved ones, caregivers, and healthcare providers, too,” said Margery Connelly, PhD, strategic director of diagnostics research and development at Labcorp. Chronic liver disease is responsible for around 2 million deaths globally every year.

Liver disease comes in a variety of forms and stems from a variety of causes, but the most widespread form of liver disease is fatty liver disease, in which too much fat builds up in the liver. Within this category exists nonalcoholic fatty liver disease, or NAFLD, more commonly referred to as metabolic dysfunction-associated steatotic liver disease (MASLD) today. Of the quarter of the global adult population who will develop MASLD, a quarter of those will develop metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). It’s a more progressive form of the disease that has a higher risk of advancing to cirrhosis and end-stage liver disease. MASH is symptomless until it enters its later stages, when patients develop either cirrhosis, which ultimately requires a liver transplant, or liver cancer, which can be fatal. Currently, the only way to diagnose MASH is through a liver biopsy, but the invasive nature of the procedure limits widespread use. The accuracy of biopsies also depends on the pathologist’s subjective interpretation.

Identifying MASH early increases the chance for patients to make the lifestyle changes needed to reverse the damage, or to receive medication. “There's a need for tests to identify this population, so they can be appropriately triaged for therapeutics,” said Arun Sanyal, MD, a fatty liver disease researcher at Virginia Commonwealth University. Over the past couple of decades, there’s been a catch-22 problem: The lack of past diagnostics meant there was little appetite for developing therapeutics, and the diagnostic world would question the point of developing diagnostics if no good therapeutics existed, Sanyal said.

An influx of noninvasive tests

This gap has spurred a new wave of noninvasive tests to fill it. There are three broad buckets of noninvasive tests emerging. The first includes simple laboratory aids based on routine tests, the most common one being the FIB-4 score, which gives an idea of how much scarring is happening in the liver and the risk of severe liver disease. It’s based on blood tests that measure platelet count, the levels of aspartate aminotransferase and alanine aminotransferase — two enzymes associated with liver function — along with a patient’s age. In routine practice, if a patient’s FIB-4 is over a certain number, they are referred for further investigation and receive a FibroScan as a secondary test. “Increasing evidence suggests that FIB-4 scores are a convenient and cost-effective way to identify patients who do not need follow up testing and care,” Connelly said.

There are other tests, such as the enhanced liver fibrosis (ELF) test. Also a blood test, it measures the burden of scar tissue in the liver and is the only test so far approved by regulatory agencies for prognostic purposes. But its use is limited by the higher cost compared with FIB-4.

New tests also identify patients with at-risk MASH, a stage in the disease when intervention significantly improves outcomes and regression of the disease. Labcorp's NASHnextTM (NIS4), a new invitro diagnostic, can identify at-risk MASH, Connelly said. The test produces a single score that identifies patients at this pivotal stage of the disease who have a higher risk of progressing to end-stage liver disease.

As a follow-up to blood tests, elastography, a type of screening, comes next. It is performed by either ultrasound or MRI-based approaches, though the cost of the latter makes them less than preferable. If an ultrasound is used, it’s typically a FibroScan, a type of scan that measures the “stiffness” of your liver, which in turn reflects the degree of scarring in the organ.

A nimble approach to new biomarkers

Although these new biomarkers are gaining traction, “much of the biomarker literature actually really lacks scientific rigor and has methodological flaws, which is why they don’t meet the regulatory bar for getting approved for specific context of use,” Sanyal said.

This lack of rigor was the driving motivation behind the creation of the Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) initiative, of which Sanyal serves as chair. The consortium was designed as a two-stage project, with the first stage aimed at analyzing existing data sets to find the leading biomarkers that could identify at-risk MASH. This stage landed on 10 noninvasive biomarkers, both blood-based and imaging-based, that showed promise for identifying people with at-risk MASH. In stage two of the project, a new prospective study will confirm the diagnostic performance of these markers for at-risk MASH.

For laboratory medicine professionals who are using these newer tests, Sanyal advised that it’s crucial to first have clarity on the robustness of the assays, as well as defining the conditions under which the samples are collected and stored. “It is really important to consider the context of use,” Sanyal said. What is the decision that will come out of it? What is the benefit versus risk of making a clinical decision based on that information?

Using existing data to cast a wider net

Even the identification of who should be tested using these biomarkers proves to be a challenging hurdle in and of itself. More often than not, the symptomless nature of liver disease means these patients go undetected until it’s too late. One patient in particular sticks in the mind of Tim Jobson, BM BCh, a liver consultant based in the United Kingdom (U.K.). The patient in question was a man in his fifties, who had simply felt a bit unwell. He had some blood tests done with his primary care physician, which turned up worrying results. He was sent for an MRI, and by the time that Jobson saw him, he had advanced liver disease and liver cancer. The man had no idea that there was anything wrong with him. Yet his blood tests, which went back 15 years, could have sounded an alarm, Jobson said. “This was all avoidable.”

Occurrences like this were not rare and served as Jobson’s motivation to found his company Predictive Health Intelligence, which has developed a tool called hepatoSIGHT. The tool incorporates historical medical data to find patients at risk of liver disease. Out of the population of around 700,000 in Somerset, U.K., where they ran the pilot, 700 patients pinged the system and were called in for further care.

“The thought process was: Well, all of these blood tests exist already, and they’re all stored electronically. We could search through those and find people with persistently abnormal tests who’ve yet to have the right interventions,” Jobson said. It hunts for certain parameters that will pick up people who either have those conditions or who are at high-risk for them, so it could be used across the broad spectrum of chronic liver disease, Jobson said.

Jobson admits the tool won’t identify everyone: It will always miss the people who haven’t had a blood test done. Another big bottleneck is the way data is siloed off in the healthcare systems in the U.K., where the trial is being run. Still, there are many people they could identify as being at risk before they even go to the hospital, he said. “This translates to tens of thousands of patients benefiting. We just need to tap into this huge and valuable data resource that’s sitting there, but that nobody can use, because they haven’t got the tool.”

The goal for the field, Sanyal said, is one day to have a validated set of tests that could be used as an initial screening to pick out patients who need follow-up testing. Ideally, these tests would be administered at the point-of-care, so that patients don’t have to jump through hoops to get tested.

More than half the adult population will be living with MASLD by 2040, experts have forecasted. The need for these tests has never been more pressing. “This could impact the way healthcare is provided to over a billion people,” Sanyal said.

Grace Browne is a freelance journalist who lives in London. She currently has a fellowship funded by the International Center for Journalists through the Health Innovation call. +Email: [email protected]