A new study published in JAMA Internal Medicine on September 21, 2026 has looked at an important question for people with fatty liver disease.
Can we identify which people with steatotic liver disease are more likely to develop cirrhosis before cirrhosis actually develops?
The answer may be yes, and one of the tools studied, called the SAFE score, showed particularly useful results for estimating future cirrhosis risk. JAMA Network
This is important because fatty liver is extremely common, but not everyone with fatty liver will develop cirrhosis.
The challenge is identifying the people who need closer follow-up.
I have discussed liver cirrhosis, investigations and treatment approaches in detail on our Homeopathy Treatment of Cirrhosis page.
What did the new study find?
Researchers from Yale School of Medicine and the VA Connecticut Healthcare System compared nine different clinical risk scores in a very large group of people with steatotic liver disease.
The study included 853,131 adults with imaging-confirmed steatotic liver disease who did not have viral hepatitis or another primary liver disease.
The patients were followed for up to 10 years to see who developed cirrhosis or hepatocellular carcinoma, a major form of liver cancer.
During the follow-up period:
- 33,794 people, or 3.96%, developed cirrhosis
- 2,978 people, or 0.35%, developed hepatocellular carcinoma
- The median age was 61 years
- About 92.7% of participants were men
- About 32.3% had diabetes
- The median BMI was 31.3 JAMA Network
The researchers compared nine risk scores, including:
- FIB-4
- APRI
- SAFE
- NAFLD Fibrosis Score
- BARD
- ALBI
- aMAP
- Tate
- and other clinical scores
The important finding was that FIB-4, APRI and SAFE showed the strongest ability to discriminate future cirrhosis risk, while SAFE, Tate and FIB-4 performed best for discriminating hepatocellular carcinoma risk. JAMA Network
But when the researchers looked at net clinical benefit, SAFE performed particularly well for predicting cirrhosis.
What is the SAFE score?
SAFE stands for Steatosis-Associated Fibrosis Estimator.
It is a non-invasive score designed to estimate the likelihood of significant liver fibrosis in people with fatty liver disease.
It uses information that is already available from routine clinical assessment, including:
- Age
- Body mass index
- Diabetes status
- AST
- ALT
- Platelet count
- Globulin level
The original SAFE score was developed as a non-invasive method to help identify patients with fatty liver disease who may have clinically important fibrosis. PubMed Central (PMC)
The new study looked at whether these types of scores could also help with a different question.
Who is more likely to develop cirrhosis over the next 10 years?
What did the SAFE score show?
In the new study, a SAFE score of 29.5 corresponded to an estimated 2.5% 10-year risk of cirrhosis at the study’s specified threshold.
At this threshold, the researchers calculated a net benefit of 0.019.
In simpler terms, the researchers estimated that using this approach could identify 1.9 additional people who went on to develop cirrhosis for every 100 people classified as being at risk, compared with the decision strategy evaluated in the analysis.
This does not mean that a SAFE score of 29.5 means a person will develop cirrhosis.
It is a risk-stratification tool.
That distinction is important.
Why is this study important?
One of the biggest problems with fatty liver disease is that many people don’t feel sick in the early stages.
You may have fatty liver on an ultrasound and feel completely normal.
Your liver enzymes may even be only mildly abnormal.
But some people with steatotic liver disease gradually develop inflammation and fibrosis.
Fibrosis means scarring of the liver.
As fibrosis progresses, some people eventually develop cirrhosis.
So the question isn’t simply:
“Do I have fatty liver?”
A more useful question is:
“Do I have fatty liver, and is there evidence that my liver is developing significant fibrosis?”
That is where non-invasive risk assessment becomes useful.
Fatty liver does not automatically mean cirrhosis
This is worth emphasising.
Most people with steatotic liver disease do not automatically progress to cirrhosis.
The JAMA study itself notes that most individuals with steatotic liver disease do not develop advanced liver disease. JAMA Network
But some people are at substantially higher risk.
Risk can be influenced by factors such as:
- Diabetes
- Obesity
- Metabolic syndrome
- High blood pressure
- Abnormal cholesterol
- Increasing age
- Persistent liver enzyme abnormalities
- Increasing fibrosis
This is why simply being told “you have fatty liver” should not be the end of the evaluation.
What is MASLD?
You may have previously heard the term NAFLD, meaning non-alcoholic fatty liver disease.
The terminology has changed.
The newer term is MASLD, or metabolic dysfunction-associated steatotic liver disease.
It describes steatotic liver disease occurring in the setting of metabolic risk factors.
These can include overweight or obesity, diabetes, high blood pressure, abnormal blood lipids and other metabolic abnormalities.
The change in terminology reflects a better understanding of the relationship between fatty liver and metabolic health. AASLD
What is the difference between fatty liver, fibrosis and cirrhosis?
These terms are often confused.
Fatty liver
Fat accumulates in the liver.
This can occur without significant scarring.
Liver fibrosis
Persistent injury can stimulate scar tissue formation.
Fibrosis is the process of scarring.
Cirrhosis
Advanced fibrosis can eventually distort the normal structure and function of the liver.
This stage is called cirrhosis.
So:
Fatty liver → inflammation/injury in some people → fibrosis → advanced fibrosis → cirrhosis
But this progression is not inevitable.
Many people remain at earlier stages.
The important point is identifying those who are at higher risk.
What is FIB-4?
FIB-4 is another commonly used non-invasive liver fibrosis score.
It uses:
- Age
- AST
- ALT
- Platelet count
The American Association for the Study of Liver Diseases, or AASLD, recognises FIB-4 as an important initial risk-assessment tool in people with suspected MASLD. AASLD
One advantage is that it is simple.
You don’t need an MRI or liver biopsy to calculate it.
However, FIB-4 is not perfect.
A low score can be useful for identifying people unlikely to have advanced fibrosis, but FIB-4 can miss some patients, particularly in certain age groups and clinical situations. AASLD
That is why a risk score should be considered part of an evaluation, not a final diagnosis.
What happens if FIB-4 is elevated?
AASLD guidance describes a pathway in which FIB-4 can be used as an initial assessment.
For many adults, a FIB-4 below 1.3 suggests a low likelihood of advanced fibrosis.
A FIB-4 of 1.3 or above generally warrants additional assessment.
A FIB-4 above 2.67 is associated with a higher likelihood of advanced fibrosis, although further assessment may still be appropriate. AASLD
Age matters too.
FIB-4 becomes less reliable in younger people and requires different interpretation in older adults. AASLD
This is why you should not look at a number on a calculator and diagnose yourself.
What tests can look for liver fibrosis without a biopsy?
This is another important development in liver medicine.
Doctors increasingly use non-invasive tests, or NITs, to assess fibrosis.
These can include:
FIB-4
A blood-test-based calculation using age, AST, ALT and platelets.
SAFE
A broader risk score that incorporates metabolic and laboratory variables.
FibroScan or VCTE
Vibration-controlled transient elastography can measure liver stiffness.
It can also provide a controlled attenuation parameter, or CAP, that helps assess liver fat. AASLD
ELF
The Enhanced Liver Fibrosis test is another blood-based fibrosis assessment.
MR elastography
MRI-based elastography can provide another assessment of liver stiffness when more detailed evaluation is required.
Liver biopsy
Biopsy is still useful in selected situations, particularly when the diagnosis is uncertain or when non-invasive tests don’t give a clear answer.
The advantage of these newer approaches is that many patients can be risk-stratified without immediately undergoing an invasive liver biopsy. AASLD
What about the risk of liver cancer?
The new study also looked at hepatocellular carcinoma, or HCC.
This is important because cirrhosis is a major risk factor for HCC.
Interestingly, the researchers found that the clinical risk scores they examined had minimal utility for deciding whether to initiate HCC screening in people who had not yet developed cirrhosis. JAMA Network
So the results should not be interpreted as:
“Calculate your SAFE score and you don’t need cancer screening.”
That is not what the study showed.
Risk scores may help with risk stratification, but decisions about liver cancer surveillance depend on the overall clinical situation and established guidelines.
Does having diabetes increase the concern?
Yes.
Diabetes is strongly associated with MASLD and more advanced liver disease.
AASLD educational guidance notes that people with diabetes and fatty liver are an important group for assessment of advanced fibrosis. AASLD
This is particularly relevant because diabetes, obesity and fatty liver frequently occur together.
A person may therefore need to think about metabolic health and liver health together, rather than treating them as separate problems.
What about obesity?
Excess body weight is another important risk factor for MASLD and progression of liver disease.
But BMI is not the whole story.
The amount and distribution of body fat, insulin resistance, diabetes, blood pressure and other metabolic factors can all matter.
This is why a person with a relatively modest BMI can still have significant metabolic risk.
Can fatty liver be reversed?
In many people, fatty liver can improve substantially when the underlying metabolic drivers are addressed.
Weight reduction is one of the most important interventions for people with MASLD who are overweight or obese.
AASLD educational material notes that a 5–10% reduction in body weight can be associated with meaningful improvements in liver fat, inflammation and fibrosis. AASLD
But the target should not simply be:
“Lose weight as quickly as possible.”
The goal is sustainable improvement in metabolic health.
This includes:
- Better diet
- Regular physical activity
- Weight management
- Diabetes control
- Managing blood pressure
- Managing cholesterol
- Avoiding excessive alcohol
- Adequate sleep
- Regular medical follow-up
Does fatty liver always cause symptoms?
No.
This is one reason fatty liver can remain unnoticed for years.
A person may have fatty liver with no obvious symptoms.
Some people experience:
- Fatigue
- Mild discomfort in the upper right abdomen
- Abdominal fullness
But symptoms are not reliable for determining how much fibrosis is present.
A person can feel perfectly well and still have advanced liver disease.
That is why risk assessment matters.
Should everyone with fatty liver get a FibroScan?
Not necessarily.
The need for FibroScan or another secondary assessment depends on the person’s overall risk and initial evaluation.
AASLD describes a pathway in which FIB-4 can be used first, followed by tests such as VCTE, ELF or other non-invasive methods when the initial risk assessment suggests further evaluation is needed. AASLD
The new JAMA study adds another piece to this evolving area by showing that SAFE may have clinical value in estimating future cirrhosis risk among people with steatotic liver disease. JAMA Network
What does this new study mean for someone with fatty liver?
For me, the most important message is not that SAFE has replaced FIB-4.
It hasn’t.
The study compared several tools, and different measures performed differently depending on what was being predicted.
The more important message is that we are getting better at identifying liver fibrosis risk without waiting for cirrhosis to appear.
That is a significant change in the way fatty liver can be approached.
Instead of simply saying:
“You have fatty liver. Lose some weight and come back later.”
we can increasingly ask:
“What is your actual risk of advanced fibrosis, and do you need further testing?”
What should you do if you have fatty liver?
If your ultrasound says:
Fatty liver
don’t panic.
But don’t ignore it either.
Ask your doctor about your:
- AST
- ALT
- Platelet count
- HbA1c
- Blood sugar
- Lipid profile
- BMI and waist circumference
- FIB-4
- Other fibrosis risk assessment where appropriate
Depending on your risk, you may need a FibroScan, ELF, MRI-based assessment or specialist review.
The aim is to identify significant fibrosis before complications develop.
A new approach to an old problem
For years, fatty liver was often treated as a relatively minor finding.
We now understand that metabolic dysfunction-associated steatotic liver disease can progress in some people to advanced fibrosis, cirrhosis and liver cancer.
At the same time, we now have increasingly sophisticated non-invasive tools to identify people who need closer assessment.
The new study of 853,131 people adds important evidence to this field.
The SAFE score showed the greatest net benefit for predicting cirrhosis in the study, while FIB-4, APRI and SAFE showed strong discrimination of cirrhosis risk. For HCC, SAFE, Tate and FIB-4 showed the strongest discrimination, but the overall clinical utility of risk scores for deciding HCC screening in people without cirrhosis was limited. JAMA Network
That distinction is important.
A risk score is a tool. It is not a diagnosis.
What I tell my patients with fatty liver
If you have been told you have fatty liver, don’t immediately jump from:
“fatty liver”
to:
“I have cirrhosis.”
They are not the same thing.
But don’t go to the other extreme and assume that fatty liver is harmless.
The right approach is to find out where you stand today.
Is it simple steatosis?
Is there evidence of fibrosis?
Are your metabolic risk factors controlled?
Do you need a FibroScan?
Do you need a hepatologist?
Do you need closer follow-up?
These are much more useful questions.
If you already have fibrosis or cirrhosis, the approach is different again.
The bottom line
This new JAMA Internal Medicine study is important because it moves the conversation beyond simply detecting fatty liver.
Researchers compared nine risk scores in more than 853,000 adults with imaging-confirmed steatotic liver disease.
Over 10 years, about 4% developed cirrhosis and 0.35% developed hepatocellular carcinoma.
FIB-4, APRI and SAFE showed strong discrimination for cirrhosis risk, while the SAFE score demonstrated the greatest net benefit for predicting cirrhosis in the study. JAMA Network
But this does not mean SAFE should be used as a standalone diagnostic test.
It means we have another potentially useful tool for identifying people who may need closer assessment.
If you have fatty liver, the important question is not only how much fat is in your liver. It is whether your liver is developing fibrosis.
That is the part we should not miss.
Sources: The primary study was published in JAMA Internal Medicine on September 21, 2026. JAMA Network Additional clinical context is based on AASLD guidance and educational material on non-invasive assessment of MASLD and liver fibrosis.
