A new discovery explains why the death rate is higher among lean patients with fatty liver disease A new discovery explains why the death rate is higher among lean patients with fatty liver disease

A new discovery explains why the death rate is higher among lean patients with fatty liver disease

A new discovery explains why the death rate is higher among lean patients with fatty liver disease

A world-first discovery has identified why lean individuals with metabolic-associated fatty liver disease (MAFLD) have a higher mortality rate than their non-thin counterparts.

The study, published in the journal Hepatology International, provides a new drug target for the development of potentially life-saving treatments, as well as the potential to increase early detection.

Fatty liver disease associated with metabolic dysfunction affects up to one-third of the world's population and is the leading cause of end-stage liver disease, liver cancer and liver transplantation.

Although it is commonly associated with overweight, obesity, and type 2 diabetes, up to 20% of individuals with metabolic fatty liver disease are considered lean.

“Despite being generally healthier than their overweight or obese counterparts, lean people with metabolic-related fatty liver disease have a worse long-term prognosis,” says the study’s first author, PhD student Mohamed Elaraby, from the Westmead Institute for Medical Research, Westmead Hospital and the University of Sydney. “We set out to understand the mechanisms behind this seemingly paradoxical outcome.”

The research team focused its efforts on telomeres, which are protective structures found at the end of chromosomes. “Telomeres protect the end of the chromosome from damage and tangling,” Al-Arabi says. “Every time a cell divides, some telomeres are cut. Eventually, the telomeres become so short that the cell dies.”

Shortening of telomeres is associated with increased morbidity and mortality in many diseases.

“We hypothesized that telomere loss increases during times of greatly increased energy demand or metabolic stress,” El-Arabi explains. “In the long term, this may lead to increased cell death and worse outcomes.”

In this study, the research team showed that growth/differentiation factor 15 (GDF-15), a protein that helps regulate a cell's response to injury, is decreased in lean individuals with fatty liver disease associated with metabolic dysfunction.

As cells try to adapt to this reduction in GDF-15, it leads to an increase in molecules known as reactive oxygen species (ROS).

An increase in ROS can damage telomeres and may lead to cell death.

“It is the combination of decreased GDF-15 and an increase in reactive oxygen compounds that leads to more rapid loss of telomeres,” El-Arabi explains. “We have been able to demonstrate that shortening of telomeres can partly explain the increased mortality rate among lean individuals with fatty liver disease associated with metabolic dysfunction.” We say “partially” because there is another factor that we believe has an impact on mortality rates.”

“As the name suggests, fatty liver is usually associated with being overweight and obese. Many health professionals do not believe that a lean person is likely to have fatty liver. This means that many lean individuals are diagnosed with metabolic fatty liver disease much later than others, leading to delayed treatment. This may also partly explain the increased mortality rate among lean individuals with metabolic fatty liver,” he continued.

The team's next step is to look for treatments that could stop the increase in ROS, reduce telomere loss and increase survival rates for lean people with metabolic-related fatty liver disease.

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