Whose liver are you calling fatty?

Hepatic steatosis, that is.

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I really dislike the medical term fatty liver. It sounds pejorative, insulting, and childish. Fatty. Cringe-worthy. And yet there it is on the radiology report we are looking at together, compelling doctor and patient to reckon with a term seemingly loaded with fat shaming and judgement. Fatty liver, found incidentally on an abdominal ultrasound, then gets stamped onto the patient’s chronic problem list. There it remains for years, decades, alongside other terms I try to avoid using like “obesity” and “non-compliance” But if you are an American reading this, then there is a 60% chance you have fatty infiltration of the liver, diagnosed yet or not.

In this post I’m going to first present some background and terminology, introducing newer terms for fatty liver such as hepatic steatosis, MASLD, and MASH. I’ll talk about how to diagnose the condition, estimate severity, and most importantly share some broad strokes on how to improve or reverse it. And finally we will examine some recent studies that caught my eye about medications that can be used along with lifestyle changes to treat fatty liver and its associated problems. Yes, Mounjaro and GLP-1 drugs help that, too!

Terminology

First of all, hang in there through this section. It confuses a lot of doctors, too. Trust me when I say that this is watered down for both you reading and me writing.

Hepatic steatosis combines two roots:

• Hepatic comes from the Greek "hepatikos" (ἡπατικός), which means “relating to the liver.” This in turn derives from "hepar" (ἧπαρ) meaning “liver.”

• Steatosis comes from the Greek "steatos" (στέατος), meaning “fat or tallow.” The "-osis" is a Greek suffix indicating “a condition or state.” Like diverticulosis, osteoporosis, halitosis.

Together, the term hepatic steatosis literally means "fatty condition of the liver." Let’s use that medical sounding label a bit more; the socially loaded fatty liver descriptor a bit less?

The short version. From larger umbrellas to more specific terms: Fatty liver/steatosis > MASLD > MASH. Fatty liver/steatosis means there is fat accumulation in the liver cells. MASLD means this is happening in people with some metabolic issues like being overweight. And MASH means there is also demonstrable inflammation in the liver.

The longer version. Hepatic steatosis is diagnosed when it is seen through imaging studies like abdominal ultrasounds and MRIs, usually when we are looking for something else like the cause of abdominal pain. Hepatic steatosis might then be further classified as Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) if the context of the whole person’s health is considered. To formally diagnose MASLD, patients must have both evidence of fatty liver/hepatic steatosis on imaging and at least one metabolic risk factor. The simplest and most common risk factor is being overweight or obese (BMI over 25), but other factors include type 2 diabetes or signs of metabolic dysfunction like high blood pressure, elevated triglycerides, low HDL cholesterol, or prediabetes.

And if we go up the ladder of severity even further, some patients will develop liver inflammation from their fatty liver/steatosis/MASLD, a condition termed MASH (Metabolic dysfunction-Associated SteatoHepatitis), which by definition needs to be confirmed through liver biopsy. Liver biopsies are rarely done without a good reason, so MASH is not as commonly diagnosed. This is not to be confused with M*A*S*H, or mobile army surgical hospital.

For our purposes, MASH specifically refers to the more severe form of MASLD in which there is active inflammation and liver cell damage as seen on biopsy. It's now recommended to use MASLD as the umbrella term, and MASH when specifically referring to the inflammatory component.

From larger umbrellas to more specific terms:

Fatty liver/steatosis > MASLD > MASH.

Good enough.

Prevalence and associations

Now, do the 60% of Americans with the largest umbrella term of fatty liver/hepatic steatosis know they have it? Most people are asymptomatic. But some patients with MASLD + МASН may complain of fatigue, malaise, and vague right upper abdominal discomfort.

The implications of MASLD extend far beyond the liver. While it can directly cause liver-specific complications like cirrhosis, liver cancer, and portal hypertension, MASLD has also been linked to numerous other health conditions. Some of these connections represent direct consequences of liver dysfunction, while others may reflect shared risk factors or bidirectional relationships.

Cardiovascular disease stands out as a particularly important association, with MASLD patients showing higher rates of atherosclerosis and heart attacks. The condition is also closely tied to metabolic disorders like type 2 diabetes and insulin resistance, creating potential vicious cycles where each condition can worsen the other. Other associated conditions include chronic kidney disease, sleep apnea, polycystic ovary syndrome, colorectal neoplasms, and thyroid problems.

Diagnosis

As stated above, usually hepatic steatosis is found on imaging studies like ultrasounds. These might be ordered as part of a work up for abnormal liver enzymes seen on blood tests, or as part of a work up for something else entirely. It’s one of the most common causes of elevated liver enzymes.

Once fatty liver/steatosis is found, doctors might order a follow up special ultrasound called a Fibroscan. This measures liver stiffness by using sound waves. Stiffer tissue indicates more scarring or fibrosis, which is what we don’t want. Should we order follow up elastograms on everyone? If you want to geek out, here are two doctor-level paragraphs to help answer that, but feel free to skip to the next boldfaced section.

In the trenches of primary care we might use a calculator tool that is cheap and quick called the FIB-4 index. It helps triage which patients are at risk of liver fibrosis and scarring. This simple calculation plugs in four variables:

• age

• two liver enzymes called AST and ALT

• platelet count

The American Gastroenterological Association thinks we should use a FIB-4 index calculator for:

• all patients with type 2 diabetes

• all patients with two or more metabolic risk factors (central obesity, high triglycerides, hypertension, insulin resistance, abnormal HDL levels, or prediabetes)

• all patients with elevated liver enzymes

• patients with hepatic steatosis already seen on any imaging study

So for example, I did this today behind the scenes for one of my patients, a 61 year old woman with diabetes and known hepatic steatosis. Fatty liver is on her chart, so I changed that over to hepatic steatosis. Her platelets were 159,000, with liver enzymes AST of 21 and ALT of 23. Her FIB-4 score came out to be 1.68. So what does that mean?

The guidelines suggest further investigation. I already know she has hepatic steatosis from an old ultrasound. But is fibrosis developing? We will see why that matters next. But in the meantime, one way to check for fibrosis is to order one of those fancy Fibroscan ultrasounds. Non-invasive.

Fibroscan are usually ordered by specialists like gastroenterologists and hepatologists, but primary care docs should be able to order them, too. Also called vibration-controlled transient elastography (VCTE), these more expensive tests measure liver stiffness, with key cutoff points:

• <8 kPa: Low risk, no significant fibrosis

• 8-12 kPa: Indeterminate, may need MRI elastography which may be limited by availability and cost, and very few family docs get into this. We would probably refer to a specialist.

• 12 kPa: Suggests advanced fibrosis/cirrhosis, needs specialist referral such as a gastroenterologist or better yet, a hepatologist.

Ok, that’s enough. Sorry. But if you have those metabolic risk factors, maybe you want to plug your most recent lab numbers into that calculator, and then talk to your doctor.

Disease course

Why is it important to recognize hepatic steatosis? First, because it is a marker of overall metabolic health. It should not be just treated with a reductionist approach that ignores the whole person. Second, it is important to watch out for progression to fibrosis and cirrhosis as this really raises red flags for the liver and overall health.

MASLD can progress from simple fatty liver to more serious liver damage over time, though the progression varies among patients. Studies show that about 36% of patients experience worsening of their liver scarring (fibrosis), while 46% remain stable, and 21% show improvement. For patients who start with minimal liver scarring, about 16% may develop advanced scarring over a 20-year period. Several factors can increase the risk of progression, including having a body mass index over 28, diabetes, being over 50 years old, and drinking alcohol.

The good news is that having MASLD without significant scarring does not increase overall death rates compared to the general population. However, once advanced scarring develops, the risks increase significantly. People with the most severe scarring (cirrhosis) have nearly 4 times higher risk of death from any cause, and about 13 times higher risk of liver-related death compared to those with minimal scarring. The most common cause of death in MASLD patients is heart disease, highlighting the importance of managing related conditions like diabetes and high cholesterol along with liver health.

Treatment of MASLD - general measures

Hepatic steatosis is just one sign among many that improvement in metabolic health is needed. I’m going to run through some consensus ways to help that do not involve medications first.

The key recommendations include refraining from alcohol, especially by avoiding heavy drinking, as it's linked to disease progression. However, a couple studies correlated light drinking with a lower risk of fibrosis. But in the absence of good quality randomized trials, almost all hepatologists I know and sources I consult feel that the less alcohol the better, all the way down to zero. Patients should receive specific immunizations, including hepatitis A and B vaccines (if not immune), pneumococcal vaccination, and standard vaccines like influenza and Covid shots.

Weight loss is considered the primary therapy for overweight or obese patients, with a target of 5-7% body weight loss at 1-2 pounds per week through lifestyle modifications. For patients with MASH, the goal increases to 7-10% weight loss. If struggling, medications or even bariatric surgery should be discussed.

Cardiovascular risk factors need to be managed, as MASLD patients have increased cardiovascular disease risk. This includes optimizing blood glucose control for diabetic patients and appropriate lipid-lowering therapy like statins for those with lipid panel problems.

Studies show that achieving at least 5% weight loss improves hepatic steatosis, while 7% or more weight loss can improve liver inflammation. Additionally, increased physical activity has been associated with lower mortality risk in MASLD patients

Medications are out there, and I’ll touch on a few below, but I will defer this personal discussion to individual patient-doctor consultations. Remember, hepatic steatosis is not an isolated condition, but rather part of a bigger picture, and should be treated that way.

But now, a few related studies and articles that caught my eye recently.

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Resmetirom, the first drug approved by the FDA for MASH

Resmetirom (Rezdiffra) became the first FDA-approved drug for treating MASH with moderate-to-advanced hepatic fibrosis in March 2024. Clinical trials showed that resmetirom recipients were more likely than placebo recipients to have MASH resolution (28% vs. 10%) and fibrosis improvement (25% vs. 14%) at 12 months, with nausea and diarrhea being the most common side effects. The manufacturer has set a yearly list price of $47,400, which incredibly “aligns with cost-effectiveness analysis by the independent Institute for Clinical and Economic Review.” While this represents a significant advancement as the first specifically approved drug for MASH with fibrosis, questions remain about its long-term clinical outcomes, safety profile, and accessibility given its whopping price point.

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Another GLP medicine in the pipeline shows big promise

This is a clipping I saved from 2023 but might as well drop in here. Eli Lilly (maker of Moujaro/Zepbound) is working on an experimental "triple G" drug called retatrutide. It showed remarkable results in treating nonalcoholic fatty liver disease, reducing liver fat by 86% in patients over 48 weeks at the highest dose, with 93% of patients achieving resolution of fatty liver disease. The drug, which targets three hormones (GLP-1, GIP, and glucagon) unlike competitors that target only one (Ozempic/Wegovy) or two (Mounjaro/Zepbound), also led to significant weight loss of 24.2% in obesity trials and showed promise in treating type 2 diabetes with meaningful reductions in blood sugar levels. The inclusion of glucagon as a target is particularly promising for liver disease treatment since this hormone has receptors directly in the liver, potentially offering better results than existing obesity drugs which have shown only 50-60% liver fat reduction.

Sounds too good to be true? Will keep watching the journals.

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Mounjaro/Zepbound study published this year shows promise, too

Earlier this year Eli Lilly also announced that their weight loss and diabetes drug tirzepatide (sold as Mounjaro/Zepbound) showed promising results in treating MASH, a fatty liver disease, with 74% of treated patients showing disease resolution compared to 13% in the placebo group after 52 weeks. While the drug was effective at clearing liver fat, its impact on liver scarring (fibrosis) was less definitive, though the company reported patients experienced meaningful improvements in their fibrosis staging. The results are particularly significant as pharmaceutical companies seek to demonstrate that these weight loss medications provide broader health benefits beyond weight loss, which could help convince reluctant insurers to cover the treatments.

For comparison, Novo Nordisk's competing drug Wegovy showed 59% MASH resolution in a similar Phase 2 study, and they are currently conducting a Phase 3 trial aimed at FDA approval for this indication.

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Another small victory for the new GLP-1 meds

A large study of 32,000 veterans compared two diabetes medications - GLP-1 agonists and DPP-4 inhibitors - to see how they affected liver disease. In patients who hadn't yet developed severe liver scarring (cirrhosis), those taking GLP-1 agonists had a 14% lower risk of their liver disease getting worse and were 11% less likely to die during the study period. While these results show GLP-1 agonists could help protect the liver in patients with both diabetes and liver disease, the medication's high cost makes it difficult for many patients to access, though it's still cheaper than the only FDA-approved liver disease drug currently available.

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Conclusion

While hepatic steatosis (formerly, and possibly impolitely known as fatty liver) affects about 60% of Americans, new terminology, diagnostic tools, and treatments are emerging to better address this condition. The progression from simple fatty liver to more serious liver damage varies among patients, but weight loss of at least 5-7% through lifestyle modifications remains the primary recommended therapy for most people. Recent FDA approval of Resmetirom and promising results from GLP-1 medications like Mounjaro and experimental drugs like retatrutide represent significant advances in medical treatment options, though cost remains a major barrier to access. Most importantly, hepatic steatosis should be viewed not as an isolated condition but as part of overall metabolic health, requiring a comprehensive approach to treatment that addresses multiple aspects of patient wellness.

Take good care, and if you are one of my patients and your chart still says fatty liver, trust that I will be amending that as soon as your next visit!