Metabolic Dysfunction-Associated Steatohepatitis (MASH)

WHAT IS MASH?

Metabolic dysfunction-associated steatohepatitis or MASH is a common, often “silent” liver disease. It resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in MASH is fat in the liver, along with inflammation and damage. Most people with MASH feel well and are not aware that they have a liver problem. Nevertheless, MASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly. MASH affects 2 to 5 percent of Americans. An additional 10 to 20 percent of Americans have fat in their liver, but no inflammation or liver damage, a condition called “fatty liver.”

3 People

DIAGNOSIS

MASH is usually first suspected in a person who is found to have elevations in liver tests that are included in routine blood test panels, such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST). When further evaluation shows no apparent reason for liver disease (such as medications, viral hepatitis, or excessive use of alcohol) and when x rays or imaging studies of the liver show fat, MASH is suspected. The only means of proving a diagnosis of MASH and separating it from simple fatty liver is a liver biopsy. For a liver biopsy, a needle is inserted through the skin to remove a small piece of the liver. MASH is diagnosed when examination of the tissue with a microscope shows fat along with inflammation and damage to liver cells. If the tissue shows fat without inflammation and damage, simple fatty liver or MAFLD is diagnosed. An important piece of information learned from the biopsy is whether scar tissue has developed in the liver. Currently, no blood tests or scans can reliably provide this information. Liver A small, slender core of tissue is removed with a biopsy needle and looked at through a microscope. Liver biopsy.

SYMPTOMS

MASH is usually a silent disease with few or no symptoms. Patients generally feel well in the early stages and only begin to have symptoms—such as fatigue, weight loss, and weakness—once the disease is more advanced or cirrhosis develops. The progression of MASH can take years, even decades. The process can stop and, in some cases, reverse on its own without specific therapy. Or MASH can slowly worsen, causing scarring or “fibrosis” to appear and accumulate in the liver. As fibrosis worsens, cirrhosis develops; the liver becomes seriously scarred, hardened, and unable to function normally. Not every person with MASH develops cirrhosis, but once serious scarring or cirrhosis is present, few treatments can halt the progression. A person with cirrhosis experiences fluid retention, muscle wasting, bleeding from the intestines, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and transplantation is increasingly performed in people with MASH. MASH ranks as one of the major causes of cirrhosis in America, behind hepatitis C and alcoholic liver disease.

CAUSES

Although MASH has become more common, its underlying cause is still not clear. It most often occurs in persons who are middle-aged and overweight or obese. Many patients with MASH have elevated blood lipids, such as cholesterol and triglycerides, and many have diabetes or pre-diabetes, but not every obese person or every patient with diabetes has MASH. Furthermore, some patients with MASH are not obese, do not have diabetes, and have normal blood cholesterol and lipids. MASH can occur without any apparent risk factor and can even occur in children. Thus, MASH is not simply obesity that affects the liver. While the underlying reason for the liver injury that causes MASH is not known, several factors are possible candidates:

  • Insulin resistance
  • Release of toxic inflammatory proteins by fat cells (cytokines)
  • Oxidative stress (deterioration of cells) inside liver cells

TREATMENT

In March 2024, the U.S. Food and Drug Administration’s first-ever approval of a treatment for metabolic dysfunction-associated steatohepatitis (MASH). Madrigal Pharmaceuticals’ Rezdiffra™ (resmetirom) has received approval for use in adults with noncirrhotic MASH with moderate to advanced liver fibrosis, as part of a regimen that includes diet and exercise.

The most important recommendations given to persons with this disease are to

  • Reduce their weight (if obese or overweight)
  • Follow a balanced and healthy diet
  • Increase physical activity
  • Avoid alcohol
  • Avoid unnecessary medications

These are standard recommendations, but they can make a difference. They are also helpful for other conditions, such as heart disease, diabetes, and high cholesterol. A major attempt should be made to lower body weight into the healthy range. Weight loss can improve liver tests in patients with MASH and may reverse the disease to some extent. Research at present is focusing on how much weight loss improves the liver in patients with MASH and whether this improvement lasts over a period of time. People with MASH often have other medical conditions, such as diabetes, high blood pressure, or elevated cholesterol. These conditions should be treated with medication and adequately controlled; having MASH or elevated liver enzymes should not lead people to avoid treating these other conditions. Experimental approaches under evaluation in patients with MASH include antioxidants, such as vitamin E, selenium, and betaine. These medications act by reducing the oxidative stress that appears to increase inside the liver in patients with MASH. Whether these substances actually help treat the disease is not known, but the results of clinical trials should become available in the next few years. Another experimental approach to treating MASH is the use of newer anti-diabetic medications—even in persons without diabetes. Most patients with MASH have insulin resistance, meaning that the insulin normally present in the bloodstream is less effective for them in controlling blood glucose and fatty acids in the blood than it is for people who do not have MASH. The newer anti-diabetic medications make the body more sensitive to insulin and may help reduce liver injury in patients with MASH. Studies of these medications—including metformin, rosiglitazone, and pioglitazone—are being sponsored by the National Institutes of Health and should answer the question of whether these medications are beneficial in MASH.