Non-Alcoholic Fatty Liver Disease (NAFLD)

Overview

Non-alcoholic fatty liver disease (NAFLD) refers to excessive fat accumulation in the liver (hepatic steatosis) in people who drink little to no alcohol and have no other dominant cause of liver fat (e.g., viral hepatitis, certain medications) [1]. NAFLD exists on a spectrum: from simple steatosis (fat without significant inflammation) to non-alcoholic steatohepatitis (NASH)&mdash;fat plus inflammation and liver-cell injury&mdash;which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [1,2].

Clinical language is shifting. Many major liver and diabetes organizations now use steatotic liver disease (SLD) as the umbrella term, with metabolic dysfunction-associated steatotic liver disease (MASLD) replacing &ldquo;NAFLD,&rdquo; and metabolic dysfunction-associated steatohepatitis (MASH) replacing &ldquo;NASH&rdquo; [2,3]. Practically, the clinical problem is the same: fatty liver driven by metabolic risk (obesity, type 2 diabetes, dyslipidemia, hypertension), with outcomes determined largely by fibrosis stage [1,2].

NAFLD/MASLD is now one of the most common chronic liver diseases globally. Recent analyses estimate adult prevalence around ~30% worldwide, and rising alongside obesity and diabetes [4,5].

Causes

NAFLD is not caused by alcohol; it is primarily a metabolic liver disease. It develops through interacting mechanisms&mdash;insulin resistance, altered lipid handling, oxidative stress, and inflammatory signaling&mdash;rather than a single trigger [1,2].

Key contributors include:

<ul>
	<li>Insulin resistance leading to increased liver fat influx and synthesis [1,2]</li>
	<li>Overweight/obesity, particularly visceral (central) adiposity [2,6]</li>
	<li>Type 2 diabetes (strongly associated; higher risk of fibrosis progression) [3,6]</li>
	<li>Dyslipidemia (high triglycerides/low HDL) and hypertension [2,6]</li>
	<li>Genetic susceptibility (e.g., variants affecting lipid metabolism) [1,2]</li>
	<li>Dietary patterns high in refined carbohydrates/added sugars and ultra-processed foods (risk amplification via caloric excess and metabolic dysregulation) [2]</li>
	<li>Sedentary lifestyle and low cardiorespiratory fitness [2]</li>
</ul>

Signs & Symptoms

NAFLD is frequently silent for years and is often discovered incidentally on blood tests or imaging [1,2]. When symptoms occur, they are typically non-specific.

Common features:

<ul>
	<li>No symptoms (most common) [1,2]</li>
	<li>Fatigue or low energy</li>
	<li>Dull discomfort/fullness in the right upper abdomen</li>
	<li>Mildly elevated liver enzymes (ALT/AST) &mdash; normal enzymes do not exclude advanced disease [1,2]</li>
	<li>Features that may suggest advanced fibrosis/cirrhosis (late findings):</li>
	<li>Abdominal swelling (ascites)</li>
	<li>Leg swelling</li>
	<li>Easy bruising/bleeding</li>
	<li>Jaundice</li>
	<li>Confusion/sleep&ndash;wake reversal (hepatic encephalopathy) [1,2]</li>
</ul>

The major clinical danger of NAFLD is progressive fibrosis, because fibrosis stage best predicts liver-related outcomes and mortality [1,2]. Complications include:

<ul>
	<li>Progression to MASH/NASH, then fibrosis and cirrhosis [1,2]</li>
	<li>Hepatocellular carcinoma (HCC), particularly in advanced fibrosis/cirrhosis (and sometimes even before cirrhosis) [1,2]</li>
	<li>Liver failure and need for transplantation in end-stage disease [1,2]</li>
	<li>Cardiometabolic and systemic risks</li>
	<li>For many patients, the leading health threat is not liver failure&mdash;it&rsquo;s vascular disease. NAFLD/MASLD is strongly associated with:</li>
	<li>Cardiovascular disease risk and events (major contributor to mortality) [4,6]</li>
	<li>Type 2 diabetes incidence and worsening glycemic control [3,6]</li>
	<li>Chronic kidney disease risk (shared metabolic pathways) [6]</li>
</ul>

Diagnosis

Diagnosis aims to confirm fatty liver, rule out other causes, and&mdash;most importantly&mdash;stage fibrosis using non-invasive tools.

Clinical evaluation

Key steps include:

<ul>
	<li>Alcohol history and review of hepatotoxic/steatogenic medications</li>
	<li>Metabolic risk assessment (weight, waist circumference, diabetes status, lipids, blood pressure) [1,2]</li>
	<li>Exclusion of other liver diseases (e.g., hepatitis B/C, autoimmune liver disease) when indicated [1,2]</li>
	<li>Laboratory tests</li>
	<li>ALT/AST, platelet count, metabolic panel, HbA1c/glucose, lipid profile</li>
	<li>Liver enzymes may be normal even in advanced fibrosis [1,2]</li>
</ul>

Imaging

<ul>
	<li>Ultrasound can detect steatosis but is less sensitive for mild disease</li>
	<li>Controlled attenuation parameter (CAP) via transient elastography or MRI-based techniques can better quantify liver fat in some settings [1,2]</li>
	<li>Fibrosis risk stratification (core step)</li>
	<li>Major guidelines recommend case-finding for fibrosis in people with metabolic risk factors (especially type 2 diabetes and obesity) using non-invasive tests (NITs) [2,3]. A common pathway is:</li>
	<li>FIB-4 (based on age, AST, ALT, platelets) as a first-line triage tool</li>
	<li>If indeterminate/high risk, proceed to transient elastography or other validated fibrosis tests</li>
	<li>Refer to hepatology for high-risk results, diagnostic uncertainty, or suspected advanced fibrosis/cirrhosis [1,2]</li>
</ul>

Liver biopsy

Biopsy is not routine for everyone. It is generally reserved when diagnosis is unclear, to confirm steatohepatitis, or to stage disease when non-invasive tests are discordant and the result will change management [1,2].

Management

Management is long-term and targets metabolic drivers and fibrosis risk, not just liver enzymes.

Lifestyle intervention (foundation for all patients)

<ul>
	<li>Guidelines consistently emphasize lifestyle change as first-line therapy [1,2]:</li>
	<li>Weight reduction: sustained weight loss improves steatosis; greater loss increases likelihood of improving inflammation and fibrosis (response is dose-dependent) [1,2]</li>
	<li>Diet quality: Mediterranean-style and whole-food dietary patterns; reduce added sugars/refined carbs; avoid excess saturated fat [2]</li>
	<li>Physical activity: regular aerobic + resistance training improves liver fat and cardiometabolic risk even independent of weight loss in some patients [2]</li>
	<li>Alcohol: even &ldquo;modest&rdquo; intake may worsen liver injury in susceptible individuals; individualized counseling is recommended [2]</li>
</ul>

Cardiometabolic risk management

<ul>
	<li>Optimize glycemic control, lipids, and blood pressure; treat obstructive sleep apnea if present</li>
	<li>Statins are generally appropriate when indicated for cardiovascular risk reduction (NAFLD itself is not a contraindication) [1,2]</li>
	<li>Pharmacologic therapy (selected patients)</li>
	<li>There is no one &ldquo;pill for NAFLD&rdquo; that fits everyone. Medication decisions depend on disease stage, comorbidities, and evolving evidence. Current guidance emphasizes:</li>
	<li>Targeting obesity/diabetes with evidence-based therapies when appropriate, as these can improve liver fat and metabolic risk [1,3]</li>
	<li>Specialist-guided therapy consideration in MASH with significant fibrosis or in high-risk patients, where emerging agents and specific indications may apply [1,7]</li>
</ul>

Monitoring and follow-up

<ul>
	<li>Periodic reassessment of metabolic risk factors and fibrosis risk with non-invasive tools</li>
	<li>Surveillance for HCC and varices is required once cirrhosis is present (specialist-directed) [1,2]</li>
</ul>

Key Points

<ul>
	<li>NAFLD is now widely framed as metabolic-driven fatty liver disease (often termed MASLD), and it is extremely common globally [2,4,5].</li>
	<li>Most patients are asymptomatic; the most important clinical task is identifying fibrosis risk early using non-invasive tests [1,2].</li>
	<li>Disease progression and outcomes are driven largely by fibrosis stage, while cardiovascular disease remains a major cause of mortality [1,4,6].</li>
	<li>Lifestyle intervention and cardiometabolic optimization are the foundation of care; pharmacologic options are increasingly relevant in higher-risk disease, typically with specialist input [1,3,7].</li>
</ul>

<h3>References</h3>

<ol>
	<li>Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., &hellip; Sanyal, A. J. (2023). AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology, 77(5), 1797&ndash;1835.</li>
	<li>Tacke, F., et al. (2024). EASL&ndash;EASD&ndash;EASO clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology, 80, 694&ndash;701. https://www.journal-of-hepatology.eu/article/S0168-8278(24)00329-5/fulltext (Journal of Hepatology)</li>
	<li>American Diabetes Association. (2025). Metabolic dysfunction-associated steatotic liver disease (MASLD) in people with diabetes and prediabetes. Diabetes Care, 48(7), 1057&ndash;1077. https://diabetesjournals.org/care/article/48/7/1057/160536/Metabolic-Dysfunction-Associated-Steatotic-Liver (Diabetes Journals)</li>
	<li>Younossi, Z. M., et al. (2023). The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology, 77(4), 1335&ndash;1347. https://pubmed.ncbi.nlm.nih.gov/36626630/ (PubMed)</li>
	<li>Amini-Salehi, E., et al. (2024). Global prevalence of nonalcoholic fatty liver disease: An updated review meta-analysis comprising a population of 78 million from 38 countries. Archives of Medical Research, 55(6), 103043. https://pubmed.ncbi.nlm.nih.gov/39094335/ (PubMed)</li>
	<li>European Association for the Study of the Liver, European Association for the Study of Diabetes, &amp; European Association for the Study of Obesity. (2024). EASL&ndash;EASD&ndash;EASO clinical practice guidelines on MASLD: Executive summary. Diabetologia, 67(11), 2375&ndash;2392. https://pubmed.ncbi.nlm.nih.gov/38869512/ (PubMed)</li>
	<li>American Association for the Study of Liver Diseases. (2025, November 7). AASLD announces update to MASLD practice guidance (including recommendations on semaglutide therapy considerations in MASH with moderate-to-advanced fibrosis). https://www.aasld.org/aasld-announces-update-metabolic-dysfunction-associated-steatotic-liver-disease-masld-practice (AASLD)</li>
</ol>

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