By skyforbes 
Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition in which excess fat builds up in the liver, affects nearly one in four Americans, according to the National Institute of Diabetes and Digestive and Kidney Diseases. Incidence of MASLD, formerly known as nonalcoholic fatty liver disease, has more than doubled over the past 20 years, according to the American Liver Foundation. The more severe form of MASLD, when fat buildup in the liver is more than 5 to 10 percent, is known as metabolic dysfunction-associated steatohepatitis (MASH). With MASH (formerly referred to as nonalcoholic steatohepatitis, or NASH) on the rise, researchers are pushing to understand more about the factors that influence the disease.
Scientists at Duke-NUS Medical School in Singapore have zeroed in on an amino acid called homocysteine, which appears to cause inflammation in people with MASH. In a two-part study published July 8, 2022, in the Journal of Hepatology, researchers looked at whether supplementing the diet with folic acid and vitamin B12 could reverse inflammation.
According to Madhulika Tripathi, MD, a senior research fellow with the laboratory of hormonal regulation in Duke-NUS Medical School’s cardiovascular and metabolic program, who co-led the study, inflammation can cause MASH to progress into cirrhosis, which can lead to liver failure or liver cancer. Although scientists know that MASH is associated with elevated levels of homocysteine, they don’t know what role it plays in the disorder.
In the first part of the study, researchers used mice and humans to determine how homocysteine levels correlated with MASH. They found that higher levels of homocysteine, called hyperhomocysteinemia, were associated with MASH progression.
“It is very important to catch NASH [MASH] at the beginning stages, when inflammation is just starting, because there are reversible and nonreversible stages. You have to catch it when the monster is first rearing its head,” says Dr. Tripathi.
The key is to treat patients before they develop the advanced stages of MASH, which causes cirrhosis, or liver scarring, explains Justin Boike, MD, a hepatologist at Northwestern Medicine in Chicago, who was not involved with the research.
While there are no drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of MASLD, lifestyle changes, particularly diet and exercise aimed at weight loss, are the go-to for treatment. “If you lose weight, your liver health improves,” says Tripathi.
According to the Mayo Clinic, people with MASLD are usually advised to lose about 10 percent of their body fat, though improvement can be seen after a 3 to 5 percent weight loss. Weight loss surgery may also be an option for some people with MASLD.
In part two of the study, Tripathi and team began to explore whether dietary supplements may work in tandem with lifestyle changes to treat severe MASLD.
The team did this by adding folic acid and vitamin B12 to the mice’s diet. They have not yet tested the supplements on humans, but the vitamins brought down liver inflammation in mice that had MASH. According to Tripathi, the inflammation reduction was significant, though she and her team could not quantify it with an exact number.
Since exact data wasn’t collected on liver inflammation and the study was done on mice, not people, the results are preliminary and cannot be applied to human health.
“Mice or mice models are designed to mimic humans as best as possible, but we know that it does not always end up being a one-to-one phenomenon. What works in mice models doesn’t always work in humans,” says Dr. Boike. “But it does set up the framework for those future studies in humans to be done.”
Currently, MASLD progression is evaluated using a sonogram and blood test. Judging by the study’s findings, it’s possible that in the future, measurement of homocysteine as a biomarker could indicate how someone’s MASH has progressed, says Tripathi.
Vitamins Have the Potential to Help
Homocysteine seems to impair an important protein called STX17, which plays a role in autophagy. Autophagy is a process that removes dead cells — which Tripathi describes as “garbage” — from the body. When these cells build up, that causes inflammation. In MASLD, this inflammation occurs in the liver specifically.
So where do vitamin B12 and folic acid come in?
“To not have homocysteine build up in your system, you have to have adequate amounts of these vitamins,” says Tripathi.
Vitamins are essential micronutrients that are involved in all bodily processes. Vitamin B12 and folic acid are specifically metabolized, stored, and activated in the liver, which is one reason that researchers believe they may play a role in liver disease.
Research published in October 2021 in the American Journal of Gastroenterology established a correlation between deficient vitamin B12 levels and MASLD, which could be caused by many things, including diabetes and obesity, but Tripathi says that it’s still unclear whether that is a coincidence or if the vitamin deficiencies caused by these conditions causes MASLD.
A meta-analysis of 33 observational studies, published in May 2021 in Nature Reviews Gastroenterology & Hepatology, found that people with MASLD were twice as likely to have type 2 diabetes than those who did not have MASLD. The authors also noted that the relationship between the two conditions is more complex than researchers previously believed.
In a study of 33 subjects published in August 2022 in Scientific Reports, researchers tested vitamin B12 in people with MASLD. They found that homocysteine levels were much higher in people with MASLD than in those without the disease, and people with MASLD were more likely to have hyperhomocysteinemia. The authors also noted a correlation between the deficiency of some vitamins — including vitamin B12, vitamin B6, and folate — and increased homocysteine levels. Researchers were not able to conclude whether vitamin B12 supplementation on its own caused lower levels of liver inflammation, since participants also lost weight during the trial, and weight loss is known to have the same effect.
It will be a few years before more research can determine whether vitamins such as B12 and folic acid could curb inflammation and prevent the disease from creating irreversible damage. Research is well underway.