Non-Alcoholic Fatty Liver Disease (NAFLD) is a common liver condition where fat accumulates in the liver cells, not caused by alcohol consumption. It ranges from simple fatty liver to more severe conditions like non-alcoholic steatohepatitis (NASH), which involves liver inflammation and damage.
NAFLD is often associated with obesity, insulin resistance, and high blood pressure. If not managed, it can lead to serious liver issues like cirrhosis and liver cancer. Lifestyle changes, such as a balanced diet and regular exercise, are crucial for managing and preventing NAFLD.
Mechanism of Fatty Liver
In people with obesity and diabetes, about 50% may also have NAFLD. NAFLD is the initial stage that can lead to liver fibrosis. Out of those with NAFLD, approximately 33% may progress to NASH, and 15% of NASH cases may develop liver fibrosis. Liver fibrosis is irreversible and cannot be cured; it can only be managed with medication and other approaches [2].
The traditional “two-hit hypothesis” suggested that excessive fat accumulation in the liver cells (first hit) followed by oxidative stress (second hit) leads to fatty liver developing into steatohepatitis and causing liver changes. However, newer research proposes a “multiple-hit hypothesis” involving factors like inflammation, gut microbiota, genetics, and diet [3].
The multi-hit hypothesis of NAFLD suggests that various factors, like diet, environment, and genetics, can contribute to insulin resistance, obesity, and changes in the gut. Insulin resistance plays a key role in NAFLD’s progression by causing the liver to store more fat and leading to fat accumulation in the liver. This fat buildup can cause damage due to high levels of fatty acids and other lipids, leading to inflammation and oxidative stress. Altered gut flora contributes to the production of fatty acids in the intestine, leading to increased absorption and circulation of molecules that activate inflammatory pathways and release proinflammatory cytokines. These factors, along with genetic predisposition, can lead to chronic liver inflammation and damage, resulting in either NASH or steatosis, depending on the specific pathways involved.
Isotope tracing has revealed how liver fat is formed [4]. About 60% of liver fat comes from fat overflow from fat cells in other parts of the body, while 26% is produced through de novo lipogenesis, the creation of new fat. Only around 15% of liver fat comes directly from dietary fat. De novo lipogenesis relies on acetyl-CoA, which mainly comes from carbohydrates (and partly from proteins). Interestingly, acetyl-CoA is usually produced in the mitochondria, but for de novo lipogenesis to occur, it needs to enter the cytoplasm when it can’t be used efficiently in the mitochondria to produce energy (ATP) [5]. This helps explain why people with high blood sugar and insulin resistance often have NAFLD. In summary, dietary fat has little impact on liver fat, but excessive intake of carbohydrates and sugars can lead to de novo lipogenesis, resulting in the accumulation of liver fat.
Weight Loss Improve Fatty Liver, But Is It a Prerequisite?
Losing weight is considered important for improving fatty liver. Studies show that reducing body weight by 7%-10% over a year can significantly enhance liver function. International clincal guidelines recommend weight loss for fatty liver patients, achieved by reducing daily calorie intake and losing 3%-5% body weight in a year. A weight loss of 7%-10% can greatly improve liver health and reduce inflammation [6]. However, to reverse liver fibrosis, a weight loss of more than 10% sustained for a year is necessary. Unfortunately, achieving such weight loss is challenging for many obese patients.
A study in 2010 supported weight loss for improving fatty liver [7]. 32 obese patients with fatty liver underwent a 48-week intervention, resulting in over 7% weight loss and significant improvement in NAFLD symptoms. However, recent research suggests that weight loss might not be necessary to improve fatty liver. A study in 2020 found that adjusting macronutrient intake, even without weight loss, can still improve fatty liver. In summary, weight loss is effective, but maintaining stable body weight can also help improve fatty liver [8].
Adjusting Macronutrient Ratios
Fatty liver can result when the liver produces more fat than it can handle [9]. Fat sources include dietary fat, fat from fat cells, and fat produced by the liver from an excess of carbohydrates. Early research in 2007 showed that a high-fat, low-carb diet could improve fatty liver [10]. In a study, obese participants following a low-carb ketogenic diet for six months experienced significant weight loss and improved fatty liver. However, not all fats are liver-friendly, and more details will be discussed in the next article.
In a clinical study from 2011, 18 participants underwent two weeks of calorie-restricted and carbohydrate-restricted diets separately [11]. The calorie-restricted group lost an average of 4 kg, while the carbohydrate-restricted group lost an average of 4.6 kg, which was not a significant difference. However, hepatic triglycerides in the calorie-restricted group decreased by 28%, whereas in the carbohydrate-restricted group, it decreased significantly by 55%. The study concluded that the two-week dietary interventions reduced liver triglycerides and improved fatty liver, but carbohydrate restriction was more effective than calorie restriction.
Low-carbohydrate diets are essential for improving NAFLD, even more than just weight loss. Changes in body weight may not reflect NAFLD severity. A study showed that a carb-rich diet for three weeks increased liver fat significantly (27%), despite a small weight gain (2%). It took a subsequent six months of calorie restriction to reduce liver fat by 25% along with a slight weight loss [12]. Excessive refined carbohydrates can accelerate fatty liver formation through hepatic lipogenesis, highlighting the importance of avoiding carb-rich diets for NAFLD prevention and management.
A 2018 study from Sweden and Finland revealed that a carbohydrate-restricted diet, with the same calorie intake, quickly reduces fatty liver and improves cardiovascular health and metabolism. It decreased hepatic lipogenesis and increased beneficial ketone bodies and serum folate, indicating improved liver function [9]. The study also found that reducing carbohydrates positively impacted gut microbiota and fatty liver reduction.
Similarly, a 2019 review from Spain showed that reducing fat and increasing carbohydrates did not effectively reduce fatty liver. Instead, a high-protein, low-carbohydrate diet was found to be the most effective in improving fatty liver [13]. Dietary sources contribute to only 15% of free fatty acids, while hepatic lipogenesis from carbohydrates is the main cause of fatty liver formation. Reducing carbohydrates is the best approach to tackle fatty liver.
Even a small increase in refined carbohydrates can significantly accumulate liver fat due to hepatic lipogenesis. Reducing refined carbohydrates is an effective way to improve fatty liver, irrespective of body weight changes.
Summary
NAFLD is a prevalent liver condition characterized by fat buildup in liver cells, not caused by alcohol. It can range from mild fatty liver to more severe NASH, causing liver inflammation and damage.
Obesity, insulin resistance, and high blood pressure are common risk factors associated with NAFLD. Proper lifestyle changes, like a balanced diet and regular exercise, play a vital role in its management and prevention.
The “multi-hit hypothesis” suggests that various factors, such as inflammation, gut health, genetics, and diet, contribute to insulin resistance and fat accumulation in the liver, leading to NAFLD.
Weight loss is an effective approach for improving NAFLD. Reducing body weight by 7%-10% over a year can significantly enhance liver function. However, maintaining stable body weight and adjusting macronutrient ratios, especially by reducing refined carbohydrates, can also lead to improvements in fatty liver.
A carbohydrate-restricted diet, even with the same calorie intake, can rapidly reduce fatty liver and improve liver health. Low-carbohydrate diets are more beneficial for NAFLD than just focusing on weight loss. Reducing refined carbohydrates is crucial to combat fatty liver, regardless of changes in body weight.
References:
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