Metabolic fatty liver disease reveals unsuspected diversity

Metabolic fatty liver disease affects more than a third of adults worldwide and is characterized by an abnormal accumulation of fat in the liver, which can progress to more serious conditions such as inflammation, fibrosis, or even cancer. Contrary to popular belief, this condition does not only affect overweight individuals or those with diabetes. It can also impact lean individuals, revealing a complexity that is often overlooked.

The mechanisms behind this disease are multiple and vary from person to person. Genetic differences play a key role: certain variations in genes such as PNPLA3 or TM6SF2 promote fat accumulation in the liver or disrupt lipid metabolism. For example, a mutation in the PNPLA3 gene reduces the activity of an enzyme essential for fat breakdown, leading to excessive fat storage in liver cells. Other genes, such as HSD17B13, may instead protect against disease progression by limiting inflammation and fibrosis.

The disease does not develop in the same way in all patients. In some, fat first accumulates in a specific area of the liver and then gradually spreads, while in others, inflammation and lesions appear earlier. These spatial and temporal variations complicate diagnosis and treatment, as a biopsy may not reflect the overall condition of the liver.

The gut microbiome also plays a central role. An imbalance in the gut flora, known as dysbiosis, promotes the passage of toxins into the bloodstream, which then reach the liver and trigger an inflammatory response. Some bacteria, such as Klebsiella pneumoniae, even produce small amounts of alcohol, worsening liver damage in genetically predisposed individuals.

Dietary habits and lifestyle also influence the progression of the disease. A diet high in sugars or saturated fats accelerates fat accumulation in the liver, while a Mediterranean diet or fiber supplements can improve the situation by modifying the microbiome. Studies show that resistant starch supplementation reduces liver fat by 8% by altering the bacterial composition of the gut.

Metabolic fatty liver disease is not limited to the liver. It is often associated with other health problems, such as cardiovascular diseases, type 2 diabetes, or kidney disorders. Affected individuals have an increased risk of developing serious complications, including certain cancers outside the liver. In women, it is frequently linked to polycystic ovary syndrome, a hormonal condition that worsens metabolic imbalances.

Symptoms are often subtle or even absent in the early stages. Some patients report fatigue or discomfort in the upper right abdomen, but most are unaware of their condition until it progresses to more advanced stages. An enlarged liver is detected in half of those affected during a physical examination.

Managing this disease requires a personalized approach. Current treatments focus on managing metabolic risk factors, such as weight loss, improving insulin sensitivity, or controlling cholesterol. However, therapies targeting specific genetic or epigenetic mechanisms are under development. For example, an experimental drug, AZD2693, significantly reduces liver fat in individuals carrying a PNPLA3 gene mutation. Other molecules, such as HSD17B13 inhibitors, show promising results in limiting inflammation and fibrosis.

Body composition also plays an important role. Lean individuals with this disease often have an abnormal fat distribution, with excess visceral fat around the organs, despite a normal body mass index. Conversely, some overweight individuals may have a relatively healthy metabolism and a lower risk of liver complications. These observations challenge the notion that obesity is the sole determining factor.

Histological differences—that is, the appearance of liver tissue under a microscope—add another layer of complexity. Certain forms of steatosis, such as microvesicular steatosis, are associated with a more severe prognosis and advanced fibrosis. However, these characteristics can vary from one area of the liver to another, making an accurate diagnosis difficult to establish from a single biopsy.

Finally, epigenetic modifications—changes in gene expression without altering their sequence—also contribute to the disease’s diversity. These modifications, influenced by the environment, diet, or lifestyle, can activate or deactivate genes involved in fat metabolism or inflammation. Nutritional interventions, such as supplementation with methyl donors (folate, choline), or drugs targeting these epigenetic mechanisms could offer new therapeutic avenues.

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Official Study Source

DOI: https://doi.org/10.1038/s44355-026-00061-3

Title: Diversity in metabolic dysfunction-associated steatotic liver disease: a framework for precision medicine

Journal: npj Gut and Liver

Publisher: Springer Science and Business Media LLC

Authors: Donghyun Ko; Jordan Low; Peter Low; Damien Chua; Yock Young Dan; Vincent Chen; Jonathan A. Fallowfield; Timothy J. Kendall; Hirokazu Takahashi; Cheng Han Ng; Nicholas Syn; Mark Muthiah