Non-alcoholic fatty liver disease (NAFLD) refers to a clinical-pathological syndrome characterized primarily by hepatic steatosis, excluding liver damage caused by alcohol or other specific factors. NAFLD encompasses non-alcoholic fatty liver (NAFL), also known as simple fatty liver, and its progression to non-alcoholic steatohepatitis (NASH; metabolic-dysfunction associated steatohepatitis, MASH), fatty liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). NAFLD has become the most common liver disease and is also an independent risk factor for cardiovascular and cerebrovascular diseases.
Etiology and Pathogenesis
NAFLD has multiple causes. High-energy diets, sugary beverages, sedentary lifestyles, obesity, type 2 diabetes, hyperlipidemia, metabolic syndrome, and malnutrition are individual or combined susceptibility factors for NAFLD. The "multiple-hit" hypothesis explains part of the disease's pathogenesis:
First Hit
Insulin resistance associated with obesity, type 2 diabetes, and hyperlipidemia leads to excessive lipid deposition within hepatocytes.
Second Hit
Lipid overload in hepatocytes results in lipid peroxidation and oxidative stress, causing mitochondrial dysfunction, the production of inflammatory factors, and activation of hepatic stellate cells, leading to inflammation and hepatocyte necrosis.
Third Hit
Inflammation mediated by gut-derived endotoxemia acts on liver cells via the portal vein, causing hepatocyte injury. This process activates hepatic stellate cells and macrophages, induces endoplasmic reticulum stress, and exacerbates liver fibrosis, further accelerating disease progression.
Additionally, gut microbiota dysbiosis is associated with NAFLD. High-fat diets reduce microbial diversity, decrease the abundance of Prevotella, and increase the ratio of Firmicutes to Bacteroidetes, enhancing intestinal energy absorption efficiency. Other factors, such as genetic predisposition, chronic psychological stress, and immune dysfunction, also contribute to the development and progression of NAFLD.
Pathology
The pathological changes in NAFLD are characterized by macrovesicular or mixed macrovesicular and microvesicular hepatic steatosis. Based on the extent of hepatic steatosis, inflammation, and fibrosis, NAFLD is classified into simple fatty liver and steatohepatitis. The latter may progress to more severe conditions such as fatty liver fibrosis, cirrhosis, or hepatocellular carcinoma.
Simple Fatty Liver
More than 30% of hepatocytes within the liver lobule exhibit steatosis, primarily macrovesicular. There is no accompanying inflammation, necrosis, or fibrosis in hepatocytes.
Steatohepatitis (NASH)
Ballooning degeneration of hepatocytes is observed in the centrilobular region (zone 3), along with focal necrosis in the lobules and inflammation in the portal area (zone 1), with or without periportal inflammation. Perisinusoidal or pericellular fibrosis occurs in zone 3 and may extend to the portal area and its surroundings, resulting in focal or widespread bridging fibrosis.
Clinical Manifestations
NAFLD typically has an insidious onset and progresses slowly, often without symptoms. A small proportion of patients may exhibit non-specific symptoms such as fatigue, mild discomfort in the right upper abdomen, dull pain in the liver area, or abdominal distension. Severe NASH may present with symptoms such as jaundice, loss of appetite, nausea, emesis, and, in some cases, hepatomegaly. When NAFLD progresses to decompensated cirrhosis, the clinical manifestations are similar to those caused by cirrhosis from other etiologies.
Laboratory and Other Examinations
Laboratory Tests
In cases of simple fatty liver disease, liver function is generally normal, or there may be a mild elevation of gamma-glutamyl transferase (γ-GT). In NASH, elevated levels of serum transaminases and γ-GT are commonly observed, with increases in ALT and AST being predominant. Some patients may also exhibit elevated triglycerides, uric acid, transferrin, fasting blood glucose, or impaired glucose tolerance.
Imaging Examinations
The accuracy of ultrasound in diagnosing fatty liver disease is approximately 70%–80%. Ultrasound can also quantify the degree of hepatic steatosis by analyzing the significant attenuation of sound waves in fatty tissues. On non-contrast CT scans, liver density is generally reduced, and a liver-to-spleen CT density ratio of ≤1 confirms the diagnosis of fatty liver disease. This ratio can also help determine the severity of the condition. Magnetic resonance spectroscopy is a reliable non-invasive method for assessing liver fat. Techniques such as ultrasound transient elastography or real-time shear wave elastography, which measure controlled attenuation parameters (CAP), can also provide quantitative evaluations of hepatic steatosis.
Pathological Examination
Liver biopsy is the primary method for confirming the diagnosis of NAFLD. It is particularly useful for distinguishing focal fatty liver disease from liver tumors and for diagnosing rare conditions such as hemochromatosis, cholesterol ester storage disease, and glycogen storage disease. Additionally, it is the most sensitive and specific method for assessing prognosis.
Diagnosis and Differential Diagnosis
The clinical diagnostic criteria for NAFLD require the presence of the following conditions:
- Presence of risk factors such as obesity, type 2 diabetes, or hyperlipidemia.
- No history of alcohol consumption, or alcohol intake equivalent to less than 140 g per week for males and less than 70 g per week for females.
- Exclusion of specific diseases that can cause fatty liver, such as viral hepatitis, drug-induced liver disease, total parenteral nutrition, Wilson’s disease, and autoimmune liver diseases.
- Imaging findings consistent with fatty liver disease.
- Histological changes in liver tissue consistent with the pathological diagnostic criteria for fatty liver disease.
Treatment
Etiological Treatment
Addressing the underlying causes, such as managing diabetes and hyperlipidemia, is effective for most cases of simple fatty liver disease and NASH. Lifestyle modifications, including low-sugar and low-fat diets and physical exercise, are critical in the treatment of NAFLD. For obese patients, a weight loss of 3%–5% can improve hepatic steatosis, while a weight loss of 7%–10% can improve liver enzyme levels, histological abnormalities, and reduce the risk of cardiovascular diseases.
Pharmacological Treatment
Simple fatty liver disease generally does not require medication, as lifestyle changes are sufficient. For NASH, particularly in cases with progressive liver fibrosis, treatments such as vitamin E, glycyrrhizin preparations, and polyunsaturated phosphatidylcholine can reduce lipid peroxidation. Insulin sensitizers such as metformin and pioglitazone, as well as glucagon-like peptide-1 (GLP-1) receptor agonists, may be used for NAFLD patients with type 2 diabetes. For those with hyperlipidemia, lipid-lowering drugs can be added to a comprehensive treatment regimen. Probiotics may help reduce endotoxin production and excessive energy absorption in the gut.
Other Treatments
For patients with a BMI >35 kg/m2 who do not respond to lifestyle changes or pharmacological treatment, bariatric surgery may be an option.
Patient Education
Diet control and increased physical activity are the most effective measures for treating obesity-related NAFLD. Weight loss should be gradual, with regular monitoring of body weight and liver function.
Nutritional imbalances should be corrected, alcohol consumption avoided, and unnecessary medications avoided. During treatment with lipid-lowering drugs, liver function should be monitored regularly under medical guidance.
Prognosis
NAFLD is an independent risk factor for cardiovascular and cerebrovascular diseases. Some cases of fatty liver inflammation may progress to cirrhosis or even liver cancer, with a prognosis similar to cirrhosis caused by viral hepatitis or alcohol. Simple fatty liver disease can fully resolve with active treatment. Fatty liver inflammation, if detected early and treated aggressively, can often be reversed.