Non-Alcoholic Fatty Liver Disease (NAFLD): What You Need to Know

Did you know that your liver may be storing too much fat even if you don’t drink alcohol? This condition, called nonalcoholic fatty liver disease NAFLD, is the most common liver disease in industrialized countries and affects around 25-35% of adults, 10% of people without obesity, and over 40% of children with obesity in the United States.

So, what exactly is NAFLD and how does it progress?

NAFLD is diagnosed when the liver contains more than 5-10% of its weight from fat. This is called steatosis and can impair the normal function of the liver and make it more vulnerable to damage. Over time, the fat accumulation triggers inflammation in the liver through the production of cytokines, which are chemical messengers that cause immune responses. This inflammation can damage the liver cells and cause non-alcoholic steatohepatitis (NASH), the more severe form of NAFLD. As the inflammation continues, scar tissue forms in the liver and replaces healthy tissue. This is called fibrosis, and it can lead to cirrhosis, which is the end stage of liver disease where most of the liver is scarred and cannot function properly.

You can think of the progression of NAFLD this way:

NAFLD → NASH → Fibrosis → Cirrhosis

NAFLD is also a risk factor for liver cancer. Even without cirrhosis, NAFLD can increase the risk of developing hepatocellular carcinoma (HCC), which is the most common type of liver cancer. Up to 45% of people with NASH can develop HCC.

What causes NAFLD?

NAFLD is caused by defects in fatty acid metabolism. This means that the body is not able to use or store fat properly. When we eat more carbohydrates than we need for energy, our body converts them into glucose (sugar). Some of this glucose is stored in the form of glycogen in our liver and muscles, but when these storage sites are full, the excess glucose is turned into triglycerides (fat) by the liver. This fat can build up in the liver cells and cause steatosis (fatty liver).

This process is worsened by insulin resistance, which is a condition where the cells do not respond well to insulin, a hormone that regulates blood glucose levels. Insulin resistance makes the body store more fat in the liver and also increases the release of fat from other tissues, such as fat cells, into the liver. Insulin resistance also affects the activity of certain molecules (PPAR-α, PPAR-γ, and SREBP1) that control the enzymes that break down or make fatty acids. When these molecules are impaired or inhibited, more fat accumulates in the liver.

Diagnosing NAFLD

NAFLD and NASH are often silent diseases that do not cause any symptoms until they’re advanced. So, it’s important to get screened for NAFLD if you have risk factors such as obesity, diabetes, high cholesterol, or high blood pressure. The earlier you detect NAFLD, the better you can prevent or treat it.

The most accurate way to diagnose NAFLD is by taking a small sample of liver tissue (biopsy) and examining it under a microscope. But this procedure is invasive and has some risks, so it is not always necessary. There are other ways to diagnose NAFLD without a biopsy.

One way is to look for risk factors that make NAFLD more likely, such as being overweight or obese, having insulin resistance, pre-diabetes or type 2 diabetes, having high triglycerides (a type of fat in the blood), or having elevated liver enzymes (a sign of liver damage). However, not all people with NAFLD have these risk factors, and not all people with these risk factors have NAFLD. Also, some people with NAFLD have normal liver enzymes, so they cannot be ruled out by a blood test alone.

Another way to diagnose NAFLD is by using imaging techniques that can show the amount of fat in the liver. These include ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). Among these, US is commonly used because it is affordable and does not expose the patient to radiation. US can also grade the severity of liver steatosis (fat) based on how bright the liver appears compared to other organs, such as the kidney. The brightness also affects how well the doctor can see the blood vessels, the liver tissue, and the diaphragm (the muscle that separates the chest from the abdomen) on the US image. The grading system for steatosis is as follows:

• Absent (score 0): The liver looks normal on US.
• Mild (score 1): The liver is slightly brighter than normal on US, but the diaphragm and the portal vein (the main blood vessel that carries blood to the liver) are still visible.
• Moderate (score 2): The liver is moderately brighter than normal on US, and the diaphragm and the portal vein are less visible.
• Severe (score 3): The liver is very bright on US, and the diaphragm and the portal vein are hardly visible or not visible at all.

US is a reliable and reasonable method to diagnose NAFLD, with high sensitivity (ability to detect true cases) and specificity (ability to exclude false cases) compared to biopsy.  However, CT imaging and MRI will yield an even greater level of accuracy.   The best imaging modality may vary depending on the patient. 

The great news is that NAFLD can be reversed if the underlying cause is reduced or removed. The main cause of NAFLD is excess carbohydrates in the diet, which are converted into glucose and then into triglycerides (fat) by the liver. When the liver cannot store or use all this fat, it accumulates in the liver cells and causes steatosis.

So, the best way to treat NAFLD is to reduce the intake of carbohydrates, especially from added sugars and high fructose corn syrup, and increase the intake of healthy fats. When we limit the consumption of sugars and starches, while increasing the intake of omega-3 fat sources, we see a metabolic shift take place.  Now the body burns fat for energy instead of glucose and produces ketone bodies, which are fat-derived molecules that can be used by the brain and other organs.

A carbohydrate-restricted diet resulting in the production of ketone bodies not only helps to lose weight and reduce fat in the liver but also creates other benefits impacting NAFLD. Ketone bodies prevent de novo lipogenesis, which is the process of making new fat from glucose. It also increases fatty acid oxidation, which is the process of breaking down fat for energy. These processes prevent further accumulation of fat in the liver and help to clear out existing fat.

A carbohydrate-restricted lifestyle can heal NAFLD through various mechanisms:

• Reduction of hunger: Ketone bodies suppress appetite and make people feel full longer. This helps to reduce calorie intake and lose weight, which are important factors for NAFLD prevention and treatment.
• Lowering of blood glucose: Ketone bodies lower blood glucose levels and prevent spikes and crashes that can damage the liver and other organs. This also helps to reduce insulin resistance. Insulin resistance is a major cause of NAFLD and its complications.
• Reduction of visceral fat: Visceral fat is the fat that surrounds the internal organs, such as the liver. Visceral fat is more harmful than subcutaneous fat, which is the fat under the skin. Visceral fat produces inflammatory chemicals that can damage the liver and increase the risk of liver cancer. Ketone bodies help to reduce visceral fat by increasing fat burning and reducing fat storage.
• Alterations in DNA signaling pathways: Ketone bodies can affect how genes are expressed in the liver cells by changing the activity of certain molecules (histone acetylases) that control how DNA is wrapped around proteins (histones). This can alter how the liver cells respond to stress, inflammation, and damage. Some of these changes can protect the liver from NAFLD progression.
• Reduction of oxidative stress: Oxidative stress is a condition where there are too many free radicals, which are unstable molecules that can damage cells and DNA. Oxidative stress can cause inflammation and fibrosis in the liver. Ketone bodies help to reduce oxidative stress by increasing the production of antioxidants, which are molecules that neutralize free radicals.
• Reduction of inflammatory cytokines: Inflammatory cytokines are chemical messengers that cause immune responses and inflammation. Inflammation can damage the liver cells and cause NASH. Ketone bodies help to reduce inflammatory cytokines by modulating the activity of certain immune cells (macrophages) that produce them.
• Reduction in Pyroptosis: Pyroptosis is a form of cell death that is triggered by pro-inflammatory signals. Pyroptosis can cause tissue damage and fibrosis in the liver. Ketone bodies help to reduce pyroptosis by blocking a molecule (NLRP3) that activates it. Blocking this pathway prevents the development of fibrosis.
• Alterations of the gut microbiome: The gut microbiome is the collection of bacteria and other microorganisms that live in the intestines. The gut microbiome can affect health in many ways, such as by influencing our metabolism, immunity, and mood. The gut microbiome can also affect liver health by producing or absorbing certain substances that can harm or protect the liver. Ketone bodies alter the gut microbiome in a way that increases the absorption and production of micronutrients such as folate, which further reduces oxidative stress.

Aside from consuming a carbohydrate-restricted diet, eating more fat from foods that contain omega-3 fatty acids can help to heal fatty liver disease and provide overall improvements in cardiometabolic health better than other forms of fat.  Omega-3 fatty acids can reduce inflammation and improve liver function. Some examples of foods that contain omega-3 fatty acids are fish, shellfish, chia seeds, flax seeds, and walnuts. 

Will I have to restrict my carbohydrates forever?

One question that many people have is whether they need to follow a very low-carbohydrate, high-fat diet for the rest of their lives to prevent fatty liver disease from coming back. This is a reasonable question since changing one’s eating habits can be challenging and sometimes inconvenient. But the benefits of this diet are well worth it and can last for a long time.

Eating very low-carbohydrate, high-fat food can improve insulin sensitivity, which is a key factor for fatty liver disease. When the cells are more sensitive to insulin, they can use glucose (sugar) more efficiently and store less fat in the liver and other tissues. So, maintaining this diet for a long time can prevent or even reverse fatty liver disease. Of course, this diet doesn’t mean eating only meat and cheese. It means eating real, whole foods that are rich in nutrients and low in sugar and processed carbohydrates. It means eating plenty of vegetables, fruits, nuts, seeds, and healthy fats. It means eating enough protein from animal or plant sources. It means nourishing your body with life-giving foods that we can grow, hunt, or fish ourselves!