Tucked away just south of the right lung lies a disease that’s quietly ravaging the world. Without fanfare, it’s been growing for the last three decades to become what some physicians believe is one of this century’s imminent public health threats. Since it was named in 1980, more than 13,000 articles have appeared in the scientific literature. Just under 500 clinical trials are underway to better understand the disease and find a treatment. It lurks in 20 to 30 percent of adults around the world and 10 to 20 percent of children in the United States. Yet because the disease has few or no symptoms, most don’t know they have it, and it can progress for years undetected. Many find out only when it’s far gone, a few steps away from cancer or organ failure.

It’s nonalcoholic fatty liver disease. Its global rise parallels the growth in related diseases like obesity and type II diabetes. But unlike obesity and diabetes, almost no one but physicians and pharmaceutical companies talk about it — despite the fact that nonalcoholic fatty liver disease costs the United States about $103 billion each year and is projected to become the leading cause for liver transplants over the next few decades. At the same time, as more of the world’s population develops the disease, the number of healthy livers available for transplants will likely decline.

“We need treatments so patients don’t progress to cirrhosis and die,” says Rohit Loomba, a physician who specializes in liver disease at the University of California, San Diego. Right now, he notes, there’s no approved FDA therapy for the later stages of the disease. Researchers are racing to find one, and to better understand the disease’s complex causes.

The liver

This roughly three-pound organ stuffed beneath your last right-side rib performs crucial functions. It filters and detoxifies the blood, stores sugars, breaks down and helps transport fats, recycles red blood cells, regulates blood clotting and helps metabolize drugs.

So, what is fatty liver disease?

Fatty liver disease is exactly what it sounds like: a liver full of fat. Having some fat in the liver is normal, but when fat accounts for more than 5 percent of the organ’s weight, the fat can become dangerous. Alcoholism has long been the best-known cause of fatty liver, but the majority of cases are considered a metabolic problem — an issue with the way the body processes and stores food.

In nonalcoholic fatty liver disease, or NAFLD, the problem starts with the buildup of excess fats. The liver normally breaks down fats into smaller pieces, which are then transported and stored in white adipose tissue in your cheeks, your gut, your thighs — all the places where you wish it wasn’t stashed. But once those reservoirs fill, excess fat, or sugars turned into fat, head to the muscles, heart, and, yes, the liver, thus developing the first stage of NAFLD called steatosis — excess fat in the liver. As fat crams into each liver cell, the cells begin to balloon, and the liver starts looking yellow and greasy. This is when the fat can turn toxic.

Changes on cellular and tissue level in fatty liver disease

Fatty liver disease covers a spectrum of conditions. When normal liver cells (left) fill with fat (white) in the first stage, there’s stress but little inflammation. Lifestyle changes and weight loss can often reverse the changes. The more serious NASH is marked by fat buildup, inflammation (black arrowhead) and ballooning of the cells (black arrows). This leads to scarring as the body tries to repair the damage. This scarring is more widespread and severe in cirrhosis, in which bands of collagen (white arrows) surround liver tissue and irreversibly disrupt its functions. Liver cancer may arise in those with NASH and cirrhosis.

Credit: J.P. ARAB ET AL / ANNUAL REVIEW OF PATHOLOGY 2018

Fat trapped in liver cells may contain free radicals, molecules that carry a highly reactive electron that, as it hunts for a partner electron, can damage vital molecules. This, as well as problems with crucial cell organelles, produces lipotoxicity (literally, fat toxicity), which stresses the cell. The cell may die or turn cancerous, signaling to inflammatory agents and leading to a type of hepatitis called nonalcoholic steatohepatitis or NASH.

The liver attempts to salvage stressed cells by repairing damage, but that can bring worse problems. Scar tissue forms around the damaged areas through a process called fibrosis and leaves functionless husks of the original cells. As fibrosis spreads, the disease may reach the fourth and last stage — cirrhosis, or severe liver damage that causes organ failure. Without a transplant, a person with cirrhosis will die.

What is known about the causes of nonalcoholic fatty liver disease?

Scientists still don’t know all the specific biological or chemical players involved in NAFLD. But there are clear associations between fatty liver disease and obesity, insulin resistance and what’s called the metabolic syndrome, a stew of conditions like high blood pressure, high blood sugar and unhealthy cholesterol levels that lead to heart problems and sometimes type II diabetes. As people live more sedentary lives, exercise less and eat more — especially too much sugar and fat — it creates prime conditions for developing a greasy liver. Genetics can also play a role, especially in people with obesity, insulin resistance or type II diabetes.

Factors influencing risk of fatty liver disease

What symptoms should you look for?

NAFLD, an umbrella term that covers both the early reversible stages of the disease and the more serious later stages, has no distinctive symptoms beyond fatigue, making diagnosis difficult and the disease likely to go undetected. Liver ballooning and eventual inflammation in NASH result in an obvious bulge and some pain in the upper right abdomen. The later stages of NASH can leave people feeling lethargic, delirious or even vomiting blood.

Physicians can do a blood test to look for liver proteins released after a liver cell dies, which can hint at inflammation. But the gold standard is a liver sample, allowing doctors to see signs of scar tissue and ballooning under a microscope and determine how far the disease has progressed. This method, though, has been brought into question not only for its invasiveness, but also for its inaccuracy. Some scientists estimate that more than 30 percent of biopsy diagnoses may be wrong. These shortcomings are the principal barrier to people accessing proper medical care, says Arun Sanyal, a gastroenterologist who studies liver disease at Virginia Commonwealth University.

That’s why a research program was approved by the Foundation of the National Institutes of Health in 2017 to find alternative, noninvasive diagnostic tools. The Non-Invasive Biomarkers of Metabolic Liver Disease effort aligns doctors with industry to develop new diagnostic screens, such as using blood or fecal samples or imaging techniques. Fibroscan, for example, uses ultrasonic sound waves to measure the liver’s stiffness, which rises with inflammation and the accumulation of scar tissue. If done correctly, Sanyal says, these stiffness measurements help doctors determine the disease stage in under 10 minutes with up to 96 percent accuracy. Another tool, magnetic resonance elastography, also measures liver stiffness but uses magnetic resonance instead of sound waves.

How prevalent is the disease? And who’s affected?

Figuring out the number of people affected by a “silent” disease like NAFLD or NASH is challenging, but scientists estimate that 14 to 32 percent of adults around the world have NAFLD, with the greatest percentages in the Middle East and South America. Approximately a third of those patients will go on to develop NASH, and a third of NASH cases can progress to cirrhosis. Given increasing rates of obesity and diabetes, the number of people with NASH is expected to triple by 2030, says Sanyal.

Who’s affected also depends on sex, age and ethnicity. Women, for example, are less susceptible to NAFLD during their reproductive years than men, but after menopause, their risk of liver disease increases. And among ethnicities, Hispanics have been found to be the most vulnerable to the disease.

Obesity and type II diabetes pose the greatest risk. Up to 80 percent of people with type II diabetes and 90 percent of those who are obese develop NAFLD.

How do you treat the disease?

For most, lifestyle changes such as weight loss, dieting and exercise can reverse the process. Even vitamin E supplements, according to several studies done in Japan, contain antioxidants that help neutralize the free radicals that threaten the liver. But for people with more advanced disease or with genes that put them at high risk, none of these options may work, which is why researchers are avidly looking for other effective treatments.

Table showing treatment for various stages of NASH

Some candidate drugs now in the pipeline target biochemical pathways involved in diabetes, such as atorvastatin (which blocks a crucial enzyme in cholesterol production) or silymarin (which prevents cell inflammation by quenching the free radicals that can harm cells). Pioglitazone, better known as Actos, increases the storage of white adipose tissue while also increasing the liver’s sensitivity to insulin and is the only diabetes drug found to be safe and effective for NASH. While there are no FDA-approved therapies specifically developed to treat fatty liver disease, there are numerous candidates in trial, according to the National Institutes of Health.

Scientists are also looking to the 1,000 or more species of bacteria living in the human gut for ideas for new therapies. Since 1982, when a study first mentioned a possible connection between NAFLD and gut microbes, scientists have identified bacteria involved the development of the disease. The link remains mysterious, but “leaky gut” syndrome may play a role. This condition, in which bacteria escape through the walls of the intestine and proliferate outside it, has in turn been linked to NAFLD. The connection suggests that altering the mix of bacteria in the gut may eventually offer another a way to control fatty liver disease.