Non-alcoholic fatty liver disease overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Parth Vikram Singh, MBBS[3]
Overview
Historical Perspective
Ludwig was the first physician to describe the non-alcoholic fatty liver disease as a separate medical entity from other fatty liver diseases.
Classification
Non-alcoholic fatty liver (NAFLD) disease may be classified into:
- Non-alcoholic fatty liver or hepatic steatosis
- Non-alcoholic steatohepatitis
Steatotic liver disease may be subclassified according to the presence of cardiometabolic risk factors, alcohol intake, and other causes of hepatic steatosis.
| Category | Definition |
| MASLD | Hepatic steatosis with at least 1 cardiometabolic risk factor, alcohol intake less than 140 g/week in women and less than 210 g/week in men, and no other known cause of hepatic steatosis |
| Metabolic dysfunction and alcohol-related liver disease (MetALD) | Hepatic steatosis with metabolic dysfunction and alcohol intake of 140-350 g/week in women or 210-420 g/week in men |
| Alcohol-associated liver disease | Alcohol intake greater than 350 g/week in women or greater than 420 g/week in men |
| Cryptogenic steatotic liver disease | Hepatic steatosis without cardiometabolic risk factors and without an identifiable cause |
| Specific-etiology steatotic liver disease | Hepatic steatosis due to another identifiable cause, such as drug-induced liver injury, iron overload, genotype 3 hepatitis C, Wilson disease, lysosomal acid lipase deficiency, hypobetalipoproteinemia, inborn errors of metabolism, celiac disease, malnutrition, or HIV infection |
(One standard drink is approximately equivalent to 10 g of alcohol, corresponding approximately to 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof distilled spirits.)
Based on liver biopsy histology, liver fibrosis in MASLD is scored using a 5-stage scale:
| Stage | Histologic description |
| F0 | Absence of fibrosis |
| F1 | Perisinusoidal or portal fibrosis |
| F2 | Perisinusoidal and portal or periportal fibrosis |
| F3 | Septal and bridging fibrosis |
| F4 | Cirrhosis |
Pathophysiology
The exact pathogenesis of NAFLD is not fully understood, but is believed due to interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation.
The pathogenesis of MASLD is multifactorial. Hepatic steatosis develops due to increased hepatic uptake of free fatty acids, increased de novo hepatic lipogenesis, decreased hepatic fatty acid oxidation, and reduced hepatic export of triglycerides into very low-density lipoproteins. Systemic insulin resistance promotes adipose tissue lipolysis and hepatic de novo lipogenesis, thereby increasing hepatic lipid accumulation. Progression from isolated steatosis to MASH is associated with lipotoxicity, in which accumulation of triglycerides, free cholesterol, saturated fatty acids, and ceramides contributes to hepatic inflammation, cellular dysfunction, and cell death. Metabolic factors, diet, genetic susceptibility, adipose tissue inflammation, and the gut microbiome may also contribute to disease progression.
Dietary factors, including high intake of glucose, fructose, saturated fats, and processed foods, may promote low-grade inflammation in the liver and extrahepatic organs. Excess adipose tissue contributes to systemic inflammation through increased release of proinflammatory cytokines and recruitment and activation of immune cells, particularly macrophages. The older two-hit hypothesis should be regarded as historical background. Current evidence supports a broader multifactorial model in which insulin resistance, lipotoxicity, diet, adipose tissue inflammation, genetics, and gut microbiome-related pathways act together to promote progression from steatosis to MASH and fibrosis.
MASLD is a multisystem metabolic disease associated with cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers, particularly gastrointestinal, breast, and gynecologic cancers.
Causes
Common causes in the development of nonalcoholic fatty liver disease is related to obesity which will result in insulin resistance and metabolic syndrome. Less commonly patients with hypertension and dyslipidemia are also associated with developing nonalcoholic fatty liver disease.
The most important clinical risk factors for MASLD are abdominal overweight or obesity, insulin resistance, prediabetes, and type 2 diabetes. The risk of developing MASLD and progressing to MASH increases with the number of metabolic syndrome features, including abdominal obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and elevated blood glucose.
Cardiometabolic risk factors used in the classification of MASLD include
- body mass index of 25 or greater, or 23 or greater in Asian individuals;
- waist circumference of 80 cm or greater in women and 94 cm or greater in men;
- fasting glucose level of 5.6 mmol/L or greater, 2-hour postload glucose level of 7.8 mmol/L or greater, hemoglobin A1c level of 5.7% or greater, established type 2 diabetes, or use of glucose-lowering medication;
- blood pressure of 130/85 mm Hg or greater or use of antihypertensive medication;
- plasma triglyceride level of 1.70 mmol/L or greater or use of triglyceride-lowering medication;
- and low HDL cholesterol.
Other contributors include older age, male sex, postmenopausal status, PNPLA3 and TM6SF2 genetic variants, sedentary lifestyle, smoking, high fructose intake, alcohol consumption above MASLD thresholds, and high-calorie diets rich in saturated fats, sugars, and processed foods.
Other known causes of hepatic steatosis that should be excluded include use of corticosteroids, methotrexate, or tamoxifen; hepatitis C virus infection; iron overload; celiac disease; HIV infection; malnutrition; Wilson disease; lysosomal acid lipase deficiency; hypobetalipoproteinemia; and inborn errors of metabolism.
Differentiating Non-alcoholic fatty liver disease from Other Diseas
Usually, NAFLD presents with no or few symptoms but if symptomatic NAFLD must be differentiated from other diseases that cause jaundice and abdominal pain which include Wilson's disease, hemochromatosis, alcoholic hepatitis, cholestatic jaundice, drug-induced liver injury, hepatitis C virus infection, celiac disease, HIV infection, malnutrition, lysosomal acid lipase deficiency, hypobetalipoproteinemia, and inborn errors of metabolism.
Epidemiology and Demographics
The estimated annual incidence of non alcoholic liver disease with steatosis in the United States is approximately 9,255 per 100,000 individuals. The prevalence of non-alcoholic liver disease in the United States is estimated to be 10,000 to 24,000 cases per 100,000 individuals annually. Non-alcoholic fatty liver disease may occur at any age, but is diagnosed most commonly in patients aged 50 to 60 years. Hepatic steatosis is more prevalent in the hispanics.
Approximately 30% to 40% of adults worldwide have MASLD. The prevalence is substantially higher among individuals with type 2 diabetes and obesity, affecting approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of individuals with obesity.
In a systematic review of 92 population-based studies from 1990 to 2019, the highest prevalence of ultrasound-detected MASLD was observed in Latin America and the lowest in Western Europe. By 2040, the global prevalence of MASLD among adults is projected to exceed 55%.
In 2021, the global age-standardized prevalence of MASLD was 15,018 per 100,000 population, and the annual incidence was 608 per 100,000 population. The prevalence was higher in men than women and peaked at 45 to 49 years of age in men and 50 to 54 years of age in women.
Among individuals with type 2 diabetes, the global pooled prevalence of MASLD based on ultrasonography was 65.3%. Among individuals with type 2 diabetes who had liver biopsy data, the global histological prevalence of MASH was 66.4%, stage F2 fibrosis was present in 40.8%, and advanced fibrosis, defined as stage F3 or F4, was present in 15.5%.
MASLD prevalence is higher in men than women. In global 2021 estimates, prevalence peaked at 45 to 49 years of age in men and at 50 to 54 years of age in women. Other risk factors for MASLD development and progression include older age, male sex, and postmenopausal status.
Risk Factors
The most potent risk factor in the development of NAFLD is obesity. Other risk factors include insulin resistance and metabolic syndrome.
Risk factors for MASLD include:
- Abdominal overweight or obesity
- Insulin resistance
- Prediabetes or type 2 diabetes
- Hypertension
- Hypertriglyceridemia
- Low HDL cholesterol
- Elevated fasting glucose or hemoglobin A1c
- Older age
- Male sex
- Postmenopausal status
- PNPLA3 and TM6SF2 genetic variants
- Sedentary lifestyle
- Smoking
- High intake of fructose, especially from sugar-sweetened beverages
- High-calorie diets rich in saturated fats, sugars, and processed foods
- Alcohol intake above MASLD thresholds
Screening
There is insufficient evidence to recommend routine screening for NAFLD in general population. However, screening is recommended in high-risk population groups(obesity, insulin resistance and patients with metabolic syndrome) as more than 50 million Americans have been estimated to have metabolic syndrome and about 80% of them have NAFD.
Universal screening for MASLD is not recommended. Current guidelines summarized in the JAMA review recommend a 2-tier testing approach to screen for advanced liver fibrosis in high-risk populations, including individuals with prediabetes or type 2 diabetes, obesity, 2 or more cardiometabolic risk factors, imaging-detected hepatic steatosis, or persistently elevated serum aminotransferase levels.
The first step is calculation of the Fibrosis-4 index, usually performed in primary care. Patients with a Fibrosis-4 index greater than 1.3 should undergo vibration-controlled transient elastography or another noninvasive test, such as the enhanced liver fibrosis test. Patients with liver stiffness greater than 8.0 kPa or an enhanced liver fibrosis test score greater than 9.8 should be referred to a hepatologist.
| FIB-4 score | Interpretation |
| <1.30 | Low risk of advanced fibrosis |
| 1.30-2.67 | Indeterminate risk of advanced fibrosis |
| >2.67 | High risk of advanced fibrosis |
Patients with a FIB-4 score less than 1.3 should undergo lifestyle modification, avoidance of alcohol intake, and treatment of type 2 diabetes, obesity, dyslipidemia, and hypertension. Repeat FIB-4 testing may be performed every 1 to 3 years. Patients with indeterminate or high-risk findings should undergo additional noninvasive fibrosis assessment and may require hepatology referral.
Natural History, Complications and Prognosis
If left untreated non alcoholic fatty liver disease may progress to fibrosis and, later cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. Common complications of NAFLD include fibrosis, cirrhosis, internal bleeding, encephalopathy. The presence of fibrosis and cirrhosisassociated with a particularly poor prognosis among patients with NAFLD.
Approximately 15% to 40% of patients with isolated hepatic steatosis progress to MASH. Fibrosis progression is usually slow, with progression of approximately 1 fibrosis stage over 14 years among patients with isolated steatosis and approximately 1 fibrosis stage over 7 years among patients with MASH. More advanced fibrosis is the strongest risk factor for progression to cirrhosis, hepatic decompensation, and liver-related mortality.
In a systematic review and meta-analysis of patients with histologically confirmed MASLD, 2% to 3% of patients with isolated steatosis developed advanced fibrosis over 15 to 20 years, while approximately 25% to 30% of patients with MASH developed advanced fibrosis within 8 to 10 years. Among patients with biopsy-confirmed MASH and F3 fibrosis, 22% progressed to cirrhosis over 2 years.
Cirrhosis is associated with hepatic decompensation events, including ascites, hepatic encephalopathy, and variceal bleeding, which occur at rates of about 10% annually. Up to nearly 2.5% of patients with cirrhosis develop incident hepatocellular carcinoma annually.
Complications of MASLD include advanced fibrosis, cirrhosis, hepatic decompensation, hepatocellular carcinoma, cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers. Hepatic decompensation events include ascites, hepatic encephalopathy, and variceal bleeding.
Fibrosis stage is the strongest prognostic factor for liver-related morbidity and mortality. Compared with patients with no fibrosis, patients with cirrhosis have substantially higher risks of liver-related events, liver-related mortality, liver transplantation, and all-cause mortality.
Cardiovascular disease is the leading cause of death in patients with noncirrhotic MASLD, followed by extrahepatic cancer and liver-related complications. In patients with MASLD-related cirrhosis, liver-related and cardiovascular disease-related deaths are the predominant causes of mortality.
MASLD is associated with increased risk of fatal and nonfatal cardiovascular events, heart failure, chronic kidney disease stage 3 or higher, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers. Extrahepatic cancers associated with MASLD include esophageal, stomach, pancreatic, colorectal, breast, and gynecologic cancers.
Diagnosis
History and Symptoms
The majority of patients with non-alcoholic fatty liver disease are asymptomatic. However, very rarely patients may complain of fatigue, malaise and dull right upper quadrant abdominal discomfort. Mild jaundice can also be noticed. Often following an asymptomatic course, the disease may present first with cirrhosis and/or the complication of portal hypertension.
MASLD is often detected incidentally when hepatic steatosis is identified on abdominal ultrasonography performed for another indication or when mild to moderate elevations in serum aminotransferase levels are found.
Physical Examination
Patients with non-alcoholic fatty liver disease usually appear normal. Physical examination of patients with non-alcoholic fatty liver disease is usually unremarkable.
Approximately 50% to 60% of patients with MASLD have mild to moderate hepatomegaly, while less than 5% have splenomegaly. More than 80% of patients are overweight or obese, 60% to 70% have atherogenic dyslipidemia, approximately 60% have prediabetes or type 2 diabetes, and up to 50% have hypertension.
Laboratory Findings
There are no specific diagnostic laboratory findings associated with non alcoholic fatty liver disease. Laboratory findings include abnormal liver function tests but are unspecific. Other laboratory tests are generally performed to rule out other diagnosis.
Normal aminotransferase levels do not exclude clinically significant MASLD. Up to two-thirds of patients with MASLD, including patients with advanced fibrosis or cirrhosis, may have normal serum aminotransferase levels, and serum ALT levels do not correlate well with histological severity.
Laboratory evaluation should include assessment of metabolic risk factors and exclusion of alternative causes of hepatic steatosis. Noninvasive fibrosis assessment commonly includes the Fibrosis-4 index and the enhanced liver fibrosis test.
Fibrosis score
The Fibrosis-4 index includes age, serum alanine aminotransferase level, serum aspartate aminotransferase level, and platelet count. It estimates the risk of advanced liver fibrosis as low when the score is less than 1.30, indeterminate when the score is 1.30 to 2.67, and high when the score is greater than 2.67. A Fibrosis-4 index less than 1.3 has a negative predictive value of 85% to 90% for detecting advanced liver fibrosis.
The enhanced liver fibrosis test uses tissue inhibitor of metalloproteinase 1, type III procollagen amino terminal peptide, and hyaluronic acid to generate a fibrosis severity score. The enhanced liver fibrosis test has a sensitivity of approximately 98% for detecting advanced liver fibrosis.
The Agile 3+ score combines liver stiffness measured by vibration-controlled transient elastography with aspartate aminotransferase to alanine aminotransferase ratio, platelet count, diabetes status, sex, and age. It may identify advanced fibrosis more accurately than the Fibrosis-4 index or liver stiffness measurement alone.
Electrocardiogram
There are no ECG findings associated with NAFLD.
X-ray
There are no x-ray findings associated with NAFLD.
Ultrasound
Ultrasound may be helpful in the diagnosis of non-alcoholic fatty liver disease. Increased echogenicity and coarsened echotexture of the liver is the most prominent and diagnostic finding on an ultrasound in patients diagnosed non-alcoholic fatty liver disease.
Abdominal ultrasonography is the first-line imaging test for diagnosis of hepatic steatosis. Sonographic findings include increased hepatic echogenicity compared with the renal cortex, decreased visibility of intrahepatic vessels, and impaired visualization of the diaphragm and deeper liver tissue.
Ultrasonography has a sensitivity of 80% to 89% and specificity of 87% to 90% for detecting moderate to severe steatosis, but sensitivity is less than 50% for mild steatosis when hepatic fat content is less than 20%.
CT scan
CT scan may be helpful in the diagnosis of non-alcoholic fatty liver disease. Findings on a CT scan diagnostic for non-alcoholic liver disease include a diffuse, low-density hepatic parenchyma without mass effect.
MRI
An MRI is one of the best tools in imaging modalities available to diagnose NAFLD. An MRI is simple to test which allows quantification of the hepatic steatosis. MRI has a sensitivity of 96% and specificity of 93% in diagnosing NAFLD. However, it uses is limited because of the cost.
Magnetic resonance imaging-proton density fat fraction has a sensitivity of 77% to 92% and specificity of 87% to 94% for detecting any degree of hepatic steatosis. Magnetic resonance spectroscopy has sensitivity and specificity of approximately 95% to 98%, but these methods are primarily used in clinical trials and specialized centers.
Other Imaging Findings
There are no other imaging findings associated with non-alcoholic fatty liver disease.
Hepattic steatosis can be measured with the Controlled attenuation parameter (CAP). The controlled attenuation parameter measures attenuation of ultrasound waves through the liver and is usually performed with vibration-controlled transient elastography. A controlled attenuation parameter value of 248 dB/m or greater is considered diagnostic for hepatic steatosis, and higher values indicate more severe steatosis. Compared with conventional ultrasonography, controlled attenuation parameter has similar sensitivity and slightly higher specificity, approximately 90%, for detecting hepatic steatosis.
Vibration-controlled transient elastography is used to noninvasively measure liver stiffness and is commonly used after FIB-4 testing in patients at increased risk for advanced fibrosis. A liver stiffness measurement greater than 8.0 kPa should prompt referral to a hepatologist for further evaluation.
Other Diagnostic Studies
Liver biopsy may be helpful in the diagnosis of non-alcoholic fatty liver disease. Findings on biopsy include macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.
Liver biopsy is the criterion standard for diagnosing MASH and staging hepatic fibrosis, but it is invasive, costly, and associated with rare acute bleeding. Liver biopsy is not typically required to diagnose MASLD, but may be useful when the etiology of liver disease is uncertain, when noninvasive tests are inconclusive, or when MASLD coexists with other liver diseases such as autoimmune hepatitis or viral hepatitis.
Treatment
Medical Therapy
Weight loss, withdrawal of hepatotoxic agents, and management of underlying insulin resistance/metabolic syndrome is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).
Resmetirom and semaglutide are conditionally approved by the US Food and Drug Administration for the treatment of adults with noncirrhotic MASH and moderate to severe fibrosis, corresponding to fibrosis stages F2 to F3. No randomized clinical trial has compared combination therapy with resmetirom and semaglutide for MASH with moderate to advanced fibrosis.
Surgery
Bariatric surgery should be considered in selected patients with MASLD and obesity with a body mass index greater than 35, especially when behavioral modification or pharmacologic treatment has not improved imaging-detected hepatic steatosis or liver fibrosis.
Bariatric surgery, including Roux-en-Y gastric bypass or sleeve gastrectomy, should be considered in selected patients with MASLD and obesity with a body mass index greater than 35, particularly in those without improvement in imaging-detected hepatic steatosis or fibrosis after behavioral modification or medication therapy.
In a bariatric surgery cohort of 180 patients with severe obesity and biopsy-proven MASH, histological resolution of MASH occurred in 84% of patients and fibrosis reduction occurred in 70% of patients at 5-year follow-up. In an observational study of 1158 adults with histologically confirmed MASH and fibrosis stages F1 to F3, bariatric surgery was associated with a lower 10-year cumulative incidence of major adverse liver-related events compared with nonsurgical care and a lower 10-year cumulative incidence of cardiovascular disease events.
Primary Prevention
Effective measures for the primary prevention of non-alcoholic fatty liver disease include maintaining a healthy weight, reducing excess caloric intake, limiting ultraprocessed foods, saturated fats, refined sugars, and sugar-sweetened beverages, engaging in regular physical activity, avoiding alcohol intake, and effectively managing type 2 diabetes, obesity, dyslipidemia, and hypertension.
Secondary Prevention
There are no established measures for the secondary prevention of non-alcoholic fatty liver disease.