Understanding Fatty Liver Disease: How It Develops, Who's at Risk, and the Treatments on the Horizon

Table of Contents

• Key Points
• Background: The Growing Problem of Fatty Liver Disease
• Clinical Disease Progression: What Happens Over Time
• Risk Factors: Who Develops NAFLD and NASH?
• Pathogenesis: The Biological Mechanisms Behind the Disease
• Where Do Liver Fats Come From?
• What Happens to Fats Inside the Liver
• The Liver's Response to Toxic Fats
• The Inflammasome: A Key Player in Liver Damage
• Insulin Resistance and Its Link to Fatty Liver
• The Gut Microbiome's Role in NAFLD
• Clinical Implications: What This Means for Treatment
• Limitations of Current Knowledge
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• NAFLD affects about 25% of the global population, with NASH rising from 20% to 27% of NAFLD patients projected by 2030.
• NASH advances one fibrosis stage every 7 years on average, while NAFL progresses about half as fast.
• The PNPLA3-I148M gene variant is the strongest genetic risk for NASH, especially combined with excess body fat.
• Liver cell injury from toxic fats triggers the inflammasome, linking metabolic stress to cell death and scarring.
• No NASH medication is approved; combination therapies and multi-target drugs are being tested in clinical trials.

Background: The Growing Problem of Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term covering a range of liver conditions that vary in how much injury and scarring (fibrosis) is present. At the milder end is nonalcoholic fatty liver (NAFL), which means fat has accumulated in liver cells (hepatic steatosis) without significant inflammation. At the more serious end is nonalcoholic steatohepatitis (NASH), a condition defined by fat accumulation plus inflammation and liver cell damage. NASH is typically accompanied by a characteristic pattern of scarring around the liver cells called pericellular fibrosis, which can eventually advance to cirrhosis — the most severe and irreversible stage of liver scarring.

The numbers behind this disease are staggering. In the United States, NAFLD cases are projected to grow from 83.1 million in 2015 (about 25% of the population) to 100.9 million by 2030. Even more concerning, the proportion of patients with the advanced form, NASH, is expected to rise from 20% to 27% of all adults with NAFLD during that same period.

This rising prevalence carries serious consequences. More patients will develop cirrhosis and end-stage liver disease requiring liver transplantation, and there will be an alarming increase in hepatocellular carcinoma (HCC), the most common type of primary liver cancer. A particularly troubling statistic: compared with other liver diseases, a much larger percentage — roughly 35% to 50% — of HCCs that arise in NASH occur before patients have cirrhosis, meaning before routine cancer screening would typically begin. As a result, these tumors tend to be larger and less amenable to curative treatments than tumors found in patients with other liver disease causes.

Globally, NAFLD affects approximately 25% of people, with the highest rates in the Middle East and South America and the lowest in Africa. While about 83% of patients with NAFLD in North America and Europe have central obesity (excess fat around the waist), a notable percentage of patients in Asia have what doctors call "lean NASH" — meaning they have a normal body mass index (BMI). It's worth noting that the BMI cutoff for defining overweight in Asia is lower (BMI greater than 23) than in North America and Europe (BMI greater than 25), reflecting differences in body composition and health risks across populations.

Diagnosis is an important challenge. While NAFL or NASH can be strongly suspected based on imaging and clinical features — such as the presence of metabolic conditions or abnormal lab tests — NASH can only be definitively diagnosed through liver biopsy. Patients with only NAFL carry a very low risk of poor outcomes, whereas having NASH increases the risk of both liver-related complications (cirrhosis, liver failure, and liver cancer) and non-liver-related problems, primarily cardiovascular disease and other malignancies.

Clinical Disease Progression: What Happens Over Time

NAFLD progresses very differently from person to person. Some patients remain stable for decades, while others advance quickly. This variability reflects the combined influences of the environment, gut microbiome, metabolism, other medical conditions (comorbidities), and genetic risk factors. Studies have shown that family members of people diagnosed with NASH have a higher risk of fibrosis, emphasizing that both genetics and potentially microbiome-related factors play important roles in disease severity.

Most patients with NASH have no symptoms and no clinically meaningful complications for years or even decades. The diagnosis is often made incidentally — found by accident during tests for other conditions — and even after identification, doctors may not fully appreciate how advanced the disease has become.

How fast does the disease progress? Based on a meta-analysis of randomized controlled trials and observational studies, patients with NASH advance about one stage of fibrosis every 7 years, using the NASH Clinical Research Network fibrosis classification system. Patients with NAFL progress about half as fast. Overall, roughly 20% of patients rapidly progress to advanced fibrosis, but doctors currently have no reliable way to identify these "rapid progressors" in advance.

The picture is further complicated by the fact that the liver damage seen on biopsy can progress, regress, or remain stable over time — meaning the disease course is not a one-way street for many patients.

Risk Factors: Who Develops NAFLD and NASH?

Metabolic syndrome is the single strongest risk factor for both NAFLD and NASH. Metabolic syndrome is defined somewhat variably, but it typically includes increased waist circumference (obesity), high blood sugar (hyperglycemia), abnormal cholesterol levels (dyslipidemia), and high blood pressure (hypertension). The relationship between NAFLD and metabolic syndrome may be bidirectional — meaning not only does metabolic syndrome raise the risk of fatty liver, but fatty liver may also worsen several features of metabolic syndrome. This suggests that effectively treating NASH could have the bonus effect of improving metabolic health.

Metabolic syndrome is also a major driver of cardiovascular events and overall death in patients with NAFLD. Among all the features of metabolic syndrome, diabetes mellitus has the clearest biological link to NAFLD progression:

• Up to 75% of people with type 2 diabetes have NAFLD
• Among diabetics with NAFLD, the rates of NASH and advanced fibrosis are higher than in non-diabetics with NAFLD, regardless of whether liver enzymes in the blood are elevated
• Patients with both NAFLD and diabetes are at increased risk of liver-related complications
• Patients with NAFLD are also at increased risk of developing diabetes in the future

Insulin resistance — the condition where the body's cells don't respond properly to insulin — has been recognized for many years as a core component of NAFLD development, and it worsens as the disease progresses. Interestingly, although improving insulin resistance does improve NASH, doing so alone may not be enough to halt disease progression.

High blood pressure (hypertension, or HTN) is another major risk factor. Fifty percent of patients with hypertension have NAFLD, and NAFLD has been linked to increased arterial stiffness, changes in heart muscle structure (myocardial remodeling), kidney disease, and heart failure. Hypertension is strongly associated with fibrosis progression. In one longitudinal study of Italian patients with NAFLD, those with hypertension had a higher risk of fibrosis progression over the 6.2-year follow-up period. There is also evidence that blocking the renin–angiotensin–aldosterone system — a hormonal pathway that contributes to high blood pressure — may improve both NASH and liver fibrosis.

Even mild fatty liver is not risk-free. While NAFL alone has traditionally been thought to carry no risk of future scarring, recent studies challenge that assumption:

• In one longitudinal study, 22% of participants with NAFL developed fibrosis and 44% developed NASH over time
• In another study, 13 of 16 patients with NAFLD and inflammation not severe enough to be diagnosed as NASH went on to develop NASH or bridging fibrosis (fibrous bands extending from one portal triad to another)

The stage of fibrosis is the clearest predictor of outcomes in patients with NASH, but steatohepatitis itself is clearly the force driving fibrosis development. The link between fibrosis and outcomes is strong, but there's substantial overlap between NASH and fibrosis severity. For example, in one study:

• 94% of patients with stage 4 fibrosis had NASH, compared to only 35% of those with stage 0 fibrosis (P < 0.001)
• Advanced fibrosis was present in 17% of those with NASH but only 2% of those without NASH

Genetics also matter. Several genetic risk factors for NASH have been identified. The best-characterized is a single-nucleotide polymorphism (a small genetic variation) in the PNPLA3 gene, which regulates the breakdown of fat droplets inside liver cells. This variant, called PNPLA3-I148M, is the genetic variant most strongly linked to NASH. Normally, the PNPLA3 protein is degraded by the cell's proteasome, but the risk-associated variant resists this breakdown and accumulates on lipid droplets, interfering with fat breakdown. Importantly, the risk of NASH in patients with this variant is maximized only when it occurs together with excess body fat — a clear example of how genes and environment work together to drive disease.

More recently, a genome-wide association study found a different genetic variant (called rs72613567:TA) in the HSD17B13 gene, which codes for a liver fat-droplet protein called 17β-hydroxysteroid dehydrogenase type 13. This variant was associated with lower levels of the liver enzymes ALT and AST in patients with fatty liver, suggesting less inflammation and liver injury. The variant produces a truncated, nonfunctional protein, implying that the normal HSD17B13 protein generates some substance that promotes liver cell damage. Pharmaceutical companies have already begun efforts to reproduce this protective effect — one company is developing an siRNA therapy to "silence" HSD17B13 and mimic the genetic protection seen in people who carry this variant.

Pathogenesis: The Biological Mechanisms Behind the Disease

For years, scientists explained NASH with a "two-hit" theory. This concept held that fat accumulation alone (the first hit) was harmless, and a second "hit" — such as oxidative stress — was required to trigger the inflammation and damage of NASH. Today, this theory is considered outdated.

Researchers now understand that many molecular pathways contribute to NASH, and it's not even certain that NASH is always preceded by simple fatty liver. Moreover, the disease drivers are likely not identical across all patients. Both the mechanisms causing the disease and its clinical features are highly heterogeneous — meaning different people reach the same end result through different biological routes.

A useful way to think about NAFLD is this: the liver's capacity to handle its primary metabolic fuels — carbohydrates and fatty acids — becomes overwhelmed, leading to the accumulation of toxic fat species. These toxic fats trigger stress, injury, and death in liver cells, which in turn leads to scarring (fibrogenesis) and genetic instability that predispose patients to cirrhosis and liver cancer. Understanding the sources and fates of fatty acids in liver cells is therefore essential to understanding the metabolic underpinnings of NASH.

Where Do Liver Fats Come From?

Fatty acids enter the liver primarily from two sources. The first is from the bloodstream, following the breakdown of triglycerides stored in adipose tissue (body fat) — a process called lipolysis that is normally regulated by insulin. When insulin signaling in fat tissue is impaired (insulin resistance), lipolysis becomes dysregulated, causing excessive delivery of fatty acids to the liver. This contributes to NASH through a specific mechanism: phosphorylation (activation) of enzymes called c-Jun N-terminal kinases (JNKs) in fat cells significantly impairs insulin signaling during inflammation. This means that inflammatory and metabolic events in body fat can drive liver disease — and may be appropriate targets for therapy. Modest weight loss improves insulin resistance in fat tissue and overall metabolic health in humans, which can benefit NASH.

The second major source of fatty acids is their production from glucose and fructose inside the liver itself, a process called de novo lipogenesis (DNL). A stable isotope study demonstrated that the increase in liver fat content in patients with NAFLD is largely driven by DNL. Here's an important difference between the two sugars:

• Glucose enters the DNL pathway in a tightly regulated manner
• Fructose is nearly completely removed from the portal blood by the liver, where it is phosphorylated and committed to DNL with almost no regulation

How much fructose actually reaches the liver's portal circulation is uncertain. Mouse studies show that gut enterocytes (intestinal lining cells) process some fructose, and human studies show the gut lining has a limited capacity to absorb fructose. However, after a large fructose load, the phosphorylation of fructose in liver cells commits it to DNL and depletes cellular energy stores (ATP) in both humans and animals, which can increase cellular stress. This helps explain why sugar-sweetened beverages containing sucrose (which breaks down into fructose and glucose in the gut) or a mixture of fructose and glucose are epidemiologically linked to fat accumulation in the liver and to NASH.

There are several potential ways to reduce liver fat production:

• Pharmacological inhibition of DNL — by targeting enzymes such as acetyl-CoA carboxylase (ACC)
• Downregulating SREBP-1c — the major transcription factor controlling DNL enzyme production; the nuclear receptor FXR regulates these enzymes and is another target
• ChREBP targeting — this protein also induces DNL enzymes, but studies of human liver biopsies show ChREBP expression is actually decreased in NASH patients, making it uncertain whether this is a viable treatment target

Another strategy is to divert energy substrates away from the liver into other tissues that can burn them. For example, PPARγ ligands such as pioglitazone (a diabetes medication) enhance fat storage in fat cells and improve NASH — but at the expense of increased peripheral fat stores and weight gain, as shown in clinical trials of these drugs in patients with type 2 diabetes.

The body's brown adipose tissue (brown fat) also metabolizes energy substrates through uncoupled mitochondrial respiration, producing heat (thermogenesis) rather than storing fat. Bile acids — which traditionally act as detergents helping absorb fat from the gut — also stimulate brown fat by binding to a receptor called TGR5, increasing thermogenesis. This has led to a proposed therapeutic strategy of increasing brown fat abundance and function to prevent or treat NASH.

What Happens to Fats Inside the Liver

Once inside liver cells, fatty acids bind to a carrier protein called fatty acid-binding protein-1 (FABP-1, also known as liver-type FABP or L-FABP). From there, they follow one of two main metabolic paths:

1. Mitochondrial β-oxidation — the breakdown of fatty acids to generate energy
2. Esterification to form triglycerides — packaging fatty acids into storage form

Some patients with NASH have mitochondrial dysfunction and impaired fat breakdown, both in the liver and possibly in other tissues throughout the body. However, it remains unclear whether an underlying defect in mitochondrial function predisposes a person to NASH, or whether the mitochondrial dysfunction is simply a consequence of the cellular stress caused by the disease.

Converting fatty acids into triglycerides is generally considered an adaptive, protective response when fat supply exceeds the liver's capacity to burn it. However, some studies suggest excess triglyceride itself may contribute to metabolic problems, rather than merely being a marker of them. Triglyceride that isn't exported into the blood as very low-density lipoprotein (VLDL) forms fat droplets inside liver cells — the defining feature of NAFLD. After a meal, the timing and location of this fat droplet breakdown is highly regulated.

A crucial mystery remains: the specific toxic fats (lipotoxic lipids) that actually damage liver cells haven't been fully identified. Candidate culprits include:

• Diacylglycerols
• Ceramides
• Lysophosphatidyl choline species

Cholesterol accumulation in the liver may also promote NASH, which is why several mouse and rat models of NASH include high-cholesterol diets to increase disease severity.

The Liver's Response to Toxic Fats

When liver cells are damaged by toxic fats, a cascade of cellular responses follows. Liver cell injury in NASH is characterized by:

• Endoplasmic reticulum (ER) stress — a condition where the cell's protein-processing factory becomes overwhelmed
• A dysfunctional unfolded protein response — the cell's attempt to fix misfolded proteins goes wrong
• Inflammasome activation — triggering inflammatory machinery
• Activation of cell death (apoptotic) pathways
• Inflammation
• An enhanced wound-healing response that leads to scarring

External factors can also modulate how vulnerable liver cells are to lipotoxic stress. These include dysregulation of cytokines and adipokines (cell-signaling molecules), depletion of cellular energy stores (ATP), toxicity from uric acid, periodic low-oxygen episodes (hypoxia) in the setting of sleep apnea, and products from the gut microbiome. The relative contribution of each of these factors likely varies among individual patients, and has not yet been fully clarified.

The Inflammasome: A Key Player in Liver Damage

Recent studies in mice have revealed that the inflammasome — a multiprotein complex inside cells — may be a critical link between initial metabolic stress and subsequent liver cell death and scarring in NASH. The inflammasome responds to two types of danger signals:

• DAMPs (danger-associated molecular patterns) — in NASH, these include saturated fatty acids produced by de novo lipogenesis
• PAMPs (pathogen-associated molecular patterns) — products of gut bacteria that travel to the liver through the portal circulation

Mouse studies show that when the inflammasome is activated in the liver, it triggers the production of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18, and promotes cell death through activation of a protein called caspase-1.

The idea of blocking the inflammasome as a treatment for NASH is appealing, but there's a catch: any therapy would need to be specifically targeted to the liver. That's because having too little inflammasome activity in the gut could actually be harmful — it might allow an increase in pro-inflammatory toll-like receptor (TLR)-4 and TLR-9 ligands in the portal circulation, which could make NASH worse.

Insulin Resistance and Its Link to Fatty Liver

Insulin resistance is a common feature of NAFLD that directly contributes to its development. It's characterized by reduced glucose disposal in non-liver tissues, including fat tissue and muscle. When fat tissue becomes insulin-resistant, it releases fatty acids inappropriately through dysregulated lipolysis, which in turn impairs insulin signaling throughout the entire body.

There is significant metabolic "crosstalk" between fat tissue and the liver. Adiponectin, IL-6, and other peptides released by fat tissue have both protective and pro-inflammatory effects in the liver. Another link between liver and fat defects may be the enzyme dipeptidyl peptidase 4 (DPP-4) — which can promote insulin resistance. In mice, circulating DPP-4 is secreted by liver cells and acts together with a blood-clotting factor called plasma factor Xa to stimulate inflammatory macrophages (immune cells) inside visceral fat tissue. This effect promotes insulin resistance, highlighting the important communication between the liver and other tissues that underlies metabolic problems in NAFLD.

The Gut Microbiome's Role in NAFLD

The dramatic rise in NAFLD over the past 25 years in developed countries has been largely attributed to a diet rich in fructose, sucrose, and saturated fats, combined with an increasingly sedentary lifestyle. But there may be another factor at play: the evolution of the human gut microbiome. This reflects both changing diets and the widespread use of antibiotics in farm animals, as well as the over-prescription of antibiotics to people.

Regardless of the cause, the evidence is compelling. Mouse studies demonstrate that a NASH-like condition can be transmitted through the microbiome — meaning gut bacteria from a mouse with NASH can transfer the disease to a healthy mouse. Human studies show that patients with NASH have a gut microbiome that is less diverse than that of healthy individuals, and weight loss also alters the microbiome. However, a cause-and-effect relationship between microbiome changes from weight loss and the resolution of NASH has not yet been established.

Clinical Implications: What This Means for Treatment

Despite steady progress in understanding how NAFLD develops and identifying potential drug targets, no medication has been approved yet for this condition. This is a major unmet need given the disease's growing prevalence. Several challenges stand in the way:

• Identifying who is at risk for NAFLD and NASH remains imprecise
• Knowledge of the disease's natural history and key drivers is incomplete
• Current laboratory and animal models don't perfectly mimic the human disease, slowing drug development
• There are no validated biomarkers (biological indicators) to predict disease risk or response to therapy — these are urgently needed

The field is moving rapidly toward combination therapies — using multiple drugs that target different pathways simultaneously. There are also single drugs being developed that have multiple cellular or molecular targets. The goal of these therapies is to arrest or even reverse disease progression.

Clinical trial design is also evolving. Researchers are developing new principles for evaluating drug efficacy that account for the disease's variable course, the need for liver biopsy confirmation, and the importance of measuring fibrosis stage — not just liver fat content — as an endpoint.

Limitations of Current Knowledge

This review highlights several important gaps in our understanding of NAFLD. The natural history of the disease is highly variable, and doctors cannot reliably predict which patients will progress rapidly versus remain stable for decades. The specific toxic fat molecules that cause liver cell injury haven't been definitively identified, making it harder to design targeted therapies. The relative contribution of different disease drivers — from genetics to gut bacteria to diet — varies among individuals, which complicates both diagnosis and treatment. Finally, the lack of validated biomarkers means that doctors must rely on liver biopsy to diagnose NASH, a procedure that carries risks and limitations.

Recommendations for Patients

Based on the evidence in this review, here are key takeaways for patients concerned about liver health:

1. Know your risk. If you have metabolic syndrome, type 2 diabetes, or high blood pressure — or a family history of NASH — talk to your doctor about whether you should be evaluated for fatty liver disease, even if your liver enzymes are normal.
2. Don't assume mild fatty liver is harmless. Even simple NAFL can progress to NASH and fibrosis over time in some patients. Regular monitoring with your healthcare provider is important.
3. Weight loss helps. Even modest weight reduction improves insulin resistance in fat tissue and overall metabolic health, which can benefit NASH. But be aware that weight loss alone may not be sufficient to reverse the disease once it's advanced.
4. Manage metabolic conditions. Controlling diabetes, blood pressure, and cholesterol — including medications that target the renin–angiotensin system — may also improve liver health.
5. Limit sugar-sweetened beverages. Fructose and sucrose-containing drinks are epidemiologically linked to liver fat accumulation and NASH, and fructose is processed by the liver in a way that promotes fat production.
6. Consider clinical trials. Since no medications are approved for NASH yet, clinical trials offer patients access to emerging therapies targeting pathways such as DNL, bile acid signaling, brown fat activation, and combination approaches. Ask your liver specialist about available studies.

Frequently Asked Questions

What is the difference between NAFLD and NASH?

NAFLD is an umbrella term for fat buildup in the liver. The milder form, NAFL, means fat without significant inflammation. NASH is more serious: fat plus inflammation and liver cell damage, often with scarring. NASH can progress to cirrhosis or liver cancer, so the distinction matters.

Who is most likely to develop fatty liver disease or NASH?

Metabolic syndrome is the strongest risk factor, especially type 2 diabetes, high blood pressure, and obesity. Up to 75% of people with type 2 diabetes have NAFLD. Family history and genetics also matter. Even some people with normal weight, especially in Asia, can develop 'lean NASH.'

How quickly does fatty liver disease progress?

Progression varies greatly. Based on a meta-analysis, patients with NASH advance about one fibrosis stage every 7 years on average, while those with NAFL progress about half as fast. About 20% of patients are rapid progressors, but doctors cannot yet predict who they are.

How is NASH diagnosed?

NASH can be suspected from imaging, lab tests, and metabolic features, but a definitive diagnosis requires a liver biopsy. There are no validated blood biomarkers yet to replace biopsy, which is invasive. Talk to your doctor if you have risk factors and abnormal liver tests.

Are there any approved medications for NASH?

No medication has been approved for NASH yet. Researchers are developing therapies that target fat production, bile acid signaling, brown fat activation, and other pathways. Many promising drugs are being tested in clinical trials. Ask a liver specialist about available studies if you are interested.

What lifestyle changes can help protect my liver?

Even modest weight loss improves insulin resistance and metabolic health, which can benefit NASH. Manage diabetes, blood pressure, and cholesterol. Limit sugar-sweetened drinks because fructose promotes liver fat production. If you have metabolic conditions or a family history, ask your doctor about screening.

If I've been told I have fatty liver disease or NASH, when should I seek a second opinion?

A second opinion is worth considering when the diagnosis or its severity is uncertain. NASH can only be definitively diagnosed by liver biopsy, and imaging and lab tests alone cannot confirm it. Because fibrosis stage is the clearest predictor of outcomes, and roughly 20% of patients progress rapidly but cannot yet be identified in advance, an independent review of biopsy findings and staging can clarify your situation. It is also reasonable when treatment options are being weighed, since no medication is approved for NASH and clinical trials may be relevant. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Mechanisms of NAFLD development and therapeutic strategies

Authors: Scott L. Friedman, Brent A. Neuschwander-Tetri, Mary Rinella, and Arun J. Sanyal

Publication: Nature Medicine, Volume 24, Issue 7, pages 908–922 (July 2018). Published online with DOI: 10.1038/s41591-018-0104-9. Author manuscript available in PMC (PubMed Central) June 2019.

Affiliations: Icahn School of Medicine at Mount Sinai; St. Louis University School of Medicine; Feinberg School of Medicine, Northwestern University; Virginia Commonwealth University.

Financial disclosure: The authors declared no competing interests.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace professional medical advice. Always consult your healthcare provider about your specific condition.