Hepatology & Internal Medicine & Family Medicine
NAFLD - Non-alcoholic fatty liver disease (NAFLD)
Non-alcoholic fatty liver disease - also known as NAFLD (Non-Alcoholic Fatty Liver Disease) or, according to the new international nomenclature adopted in 2023, MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease) - is the abnormal accumulation of fat (triglycerides) in hepatocytes representing more than 5 % of liver weight, in the absence of significant alcohol consumption (less than 20 g/day in women and 30 g/day in men) and in the presence of at least one metabolic risk factor. With a worldwide prevalence estimated at 25 to 30 % of the general adult population - reaching 70 to 90 % in obese or type 2 diabetic patients - NAFLD/MASLD is today the most common chronic liver disease worldwide, and represents the fastest-growing indication for liver transplantation in Western countries. The spectrum of the disease ranges from simple benign steatosis (without inflammation or fibrosis) to non-alcoholic steatohepatitis (NASH or MASH), an inflammatory form associated with hepatocyte lesions (hepatocyte ballooning, Mallory-Denk bodies) and progressive fibrosis that can progress over decades to cirrhosis and its complications - portal hypertension, hepatocellular insufficiency, hepatocellular carcinoma (HCC). NAFLD is the hepatic manifestation of the metabolic syndrome: abdominal obesity, insulin resistance, type 2 diabetes, dyslipidemia and arterial hypertension are the main cofactors. Long lacking a specific drug treatment, 2024 marked a turning point with FDA approval of resmetirom (Rezdiffra®), the first drug specifically indicated for NASH/MASH with advanced fibrosis in adults, while GLP-1 receptor agonists (semaglutide, tirzepatide) are transforming management by simultaneously acting on weight, insulin resistance and liver histology.
Pathophysiology and mechanisms of progression
- Insulin resistance and hepatic lipid flux : insulin resistance in adipose tissue lifts inhibition of lipolysis → increased flow of non-esterified fatty acids (NEFA) to the liver via the portal vein + hepatic insulin resistance increases de novo lipogenesis (hepatic synthesis of triglycerides from glucose) and reduces mitochondrial beta-oxidation → accumulation of triglycerides in hepatocytes → steatosis
- Lipotoxicity and oxidative stress - mechanisms of NASH : toxic lipid species (ceramides + diacylglycerols + saturated free fatty acids) accumulate in hepatocytes → activation of oxidative stress pathways + endoplasmic reticulum stress + programmed cell death (apoptosis + necroptosis) → hepatocyte ballooning + Mallory-Denk bodies + necrosis → histological definition of NASH
- Liver inflammation and the gut-liver axis: injured hepatocytes release danger signals (DAMPs) → activation of Kupffer cells (hepatic resident macrophages) via TLR4 receptors → pro-inflammatory cytokines (TNF-α + IL-6 + IL-1β) → steatohepatitis + intestinal dysbiosis increases intestinal permeability → passage of bacterial LPS to the liver via the portal vein (intestine-liver axis) → amplification of hepatic inflammation
- Fibrogenesis by hepatic star cells : inflammatory signals (TGF-β + PDGF) and oxidative stress activate quiescent hepatic star cells → transformation into collagen-producing myofibroblasts → progressive fibrosis (F0 → F1 → F2 → F3 → F4 cirrhosis) + once advanced fibrosis (F3-F4) has set in → spontaneous regression difficult even with correction of metabolic factors
- Genetic modifiers : rs738409 (I148M) variant of the PNPLA3 gene → doubled risk of NAFLD and NASH + TM6SF2 E167K variant → increased risk of advanced fibrosis + HSD17B13 protective variant → reduced risk of NASH and fibrotic progression → explain interindividual variability in severity for the same level of exposure to metabolic factors
Disease spectrum and nomenclature (NAFLD / MASLD 2023)
| Entity (old / new nomenclature) | Histological definition | Prevalence and prognosis |
|---|---|---|
| Simple steatosis (NAFL / MASLD pure steatosis) | Triglyceride accumulation in > 5 % hepatocytes - without significant lobular inflammation - without hepatocyte ballooning - without fibrosis | 80 % of NAFLD + generally benign prognosis + progression to NASH in 10 to 25 % of cases over 5 to 10 years + low risk of cirrhosis but increased cardiovascular morbidity independent of fibrosis |
| Non-alcoholic steatohepatitis (NASH / MASH) | Steatosis + lobular inflammation + hepatocyte ballooning ± Mallory-Denk bodies ± perisinusoidal and portal fibrosis - NAS score ≥ 4 required for histological diagnosis - fibrosis graded F0 to F4 | 20 % of NAFLD + 30 to 40 % progress by at least one fibrosis stage over 5 years + cirrhosis risk at 15-20 years of 10 to 15 % of confirmed NASH + leading cause of liver transplantation increasing in Canada |
| Advanced fibrosis NAFLD (F3) | Bridging fibrosis without completely distorted architecture | Annual risk of HCC of 0.5 to 1 % even without established cirrhosis - particularity of NAFLD compared to viral hepatitis + biannual monitoring by ultrasound ± AFP indicated from stage F3 onwards |
| Cirrhosis NAFLD/MASLD (F4) | Extensive fibrosis - distorted liver architecture - regenerative nodules - portal hypertension | Annual HCC risk of 1 to 2 % + potential indication for liver transplantation + endoscopic monitoring (esophageal varices) + mandatory specialized hepatological follow-up |
| Hepatocellular carcinoma (HCC) in NAFLD | Malignant transformation on NAFLD cirrhosis (60-70 % of HCC on NAFLD) or without prior cirrhosis (30-40 % - important feature distinguishing NAFLD from viral hepatitis) | Increasing proportion of all HCC in Canada and Quebec + HCC can occur without established cirrhosis → limits the effectiveness of surveillance programs based on cirrhosis alone |
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The new MASLD nomenclature (2023) replaces NAFLD and NASH with the terms MASLD (steatosis associated with metabolic dysfunction) and MASH (steatohepatitis associated with metabolic dysfunction), eliminating the exclusionary definition in favor of a positive one based on the presence of at least one metabolic risk factor (obesity + diabetes + dyslipidemia + hypertension + overweight with increased waist circumference). The two nomenclatures coexist in the current literature; the terms NAFLD and NASH are still widely used in Quebec in current practice.
Risk factors and populations to watch out for
| Risk factor | Prevalence of NAFLD in this group | Mechanism and clinical remarks |
|---|---|---|
| Obesity (BMI ≥ 30 kg/m²) | 60 to 90 % | Visceral obesity (waist circumference > 102 cm in men and > 88 cm in women) is more strongly associated with NAFLD than BMI alone + correlates with histological severity + weight loss > 7 to 10 % histologically improves steatosis and NASH |
| Type 2 diabetes | 50 to 75 % | Severe insulin resistance + increased risk of NASH and advanced fibrosis regardless of degree of obesity + some antidiabetic agents (GLP-1 agonists + pioglitazone + SGLT-2 inhibitors) have a demonstrated histological liver benefit → preferential choices in NAFLD patients + type 2 diabetes |
| Hypertriglyceridemia and hypo-HDLemia | 50 to 80 % for hypertriglyceridemia | Reflects increased hepatic lipogenesis and insulin resistance + classic components of metabolic syndrome + elevated fasting triglycerides are an indirect marker of hepatic steatosis |
| Hypertension | 30 to 70 % | Metabolic syndrome component + independent association with advanced liver fibrosis in some prospective studies |
| NAFLD without obesity (lean NAFLD) | 7 to 20 % normal weight people | Insulin resistance despite normal BMI + relative visceral adiposity (prominent abdomen with normal BMI) + genetic predisposition (PNPLA3) + may be as severe histologically as obesity-associated NAFLD + particularly common in South and East Asia |
Clinical presentation and initial laboratory work-up
- Asymptomatic in 80 to 90 % of cases: fortuitous discovery on abdominal ultrasound prescribed for another indication or during transaminase elevation on routine workup + when present - discomfort or heaviness in right hypochondrium (moderate hepatomegaly) + unexplained chronic asthenia + mild nausea - no symptoms are specific or correlated with histological severity
- Transaminases (ALT/ASAT) : ALT (ALAT) typically higher than AST (ASAT) - AST/ALT ratio < 1 in simple steatosis (inverse ratio in alcoholic cirrhosis) + moderate elevation in simple steatosis (1 to 2 times normal) → more marked in NASH (2 to 5 times) + normal transaminases do not exclude NAFLD or advanced fibrosis - 20 to 30 % of patients with histologically confirmed NASH have transaminases in the normal range
- Gamma-GT (GGT) frequently elevated: reflects enzymatic induction by hepatic steatosis and insulin resistance + GGT > 3 times normal combined with elevated ALT points to NASH
- Associated metabolic workup essential: fasting blood glucose + HbA1c + complete lipid profile (TG + HDL + LDL) + waist circumference + BMI - essential elements to be systematically evaluated in all cases of NAFLD to quantify overall metabolic and cardiovascular risk.
- Exclusion etiological work-up : hepatitis B (HBsAg) and C (anti-HCV Ac) serologies + autoimmune workup (ANA + ASMA + anti-LKM1) for autoimmune hepatitis + ferritin and transferrin saturation for hereditary hemochromatosis + ceruloplasmin for Wilson's disease (subjects) < 40 years) + alpha-1-antitrypsin + detailed alcohol consumption - to exclude any other cause of chronic liver disease before retaining the diagnosis of NAFLD
Non-invasive diagnosis of fibrosis stage
The stage of liver fibrosis - not steatosis or NASH - is the main determinant of long-term prognosis in NAFLD. The aim is to identify patients with advanced fibrosis (F3-F4) requiring intensified monitoring and priority treatment:
| Diagnostic tool | Method and availability in Quebec | Diagnostic performance and indications |
|---|---|---|
| FIB-4 (Fibrosis-4 score) - first intention | Score calculated from age + platelets + AST + ALT: FIB-4 = (age × AST) / (platelets × √ALT) + free calculation online or on mobile app + no additional cost + usable from the first primary care consultation | First-line test recommended by AASLD and EASL + FIB-4 2.67: advanced fibrosis likely → liver elastography recommended + intermediate zone 1.30-2.67: elastography to refine assessment + to be recalculated annually in patients at risk |
| Liver elastography (FibroScan® - transient elastography) | Measurement of hepatic stiffness in kPa by ultrasonography + non-invasive + painless + takes 5 to 10 minutes + CAP module simultaneously measures steatosis in dB/m + available in specialized hepatology centers and some gastroenterology clinics in Quebec + requires a 2-hour fast. | Non-invasive reference method for fibrosis assessment + NAFLD thresholds: 12 to 14 kPa → severe fibrosis or cirrhosis (F3-F4) + limitations: results distorted by morbid obesity (BMI > 40) + acute liver inflammation (ALT > 5× normal) + ascites + insufficient fasting |
| Hepatic MRI with spectroscopy and elastography (MRE) | Quantification of steatosis by MRI-PDFF (proton density fraction) + measurement of hepatic rigidity by MRI elastography + limited availability and high cost in current practice in Quebec | Most accurate non-invasive method for simultaneously quantifying steatosis and assessing fibrosis + MRI-PDFF correlates better with histology than conventional ultrasound + gold standard endpoint in therapeutic NAFLD/MASH clinical trials |
| Liver biopsy - the histological gold standard | Ultrasound-guided percutaneous sampling + histological analysis with NAS score (NAFLD Activity Score scoring steatosis + inflammation + bloating) and Brunt-Kleiner fibrosis score (F0 to F4) + risk of clinically significant bleeding 1/500 to 1/1000 + post-procedure pain in 30 % of cases | Reserved for situations where non-invasive methods are discordant or insufficient + or prior to inclusion in a clinical trial + or when a histological differential diagnosis is required (autoimmune hepatitis + drug-induced hepatitis) + NAS score ≥ 4 required to retain the diagnosis of NASH + possible sampling error (intrahepatic variability of fibrosis) |
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Cardiovascular disease (myocardial infarction + stroke) is the leading cause of death in NAFLD - overtaking liver-related causes - whatever the stage of fibrosis. Assessment and management of overall cardiovascular risk (statins + antihypertensives + antiplatelet agents according to individual risk score) are as essential a component of any NAFLD patient's follow-up as liver monitoring. Statins are not contraindicated in NAFLD - they are safe and recommended if the cardiovascular risk justifies it.
Treatment - lifestyle modifications, medication and monitoring
- Weight loss through lifestyle modification - the central therapeutic goal : loss of 5 % of weight → improves steatosis + loss of 7 to 10 % → improves lobular inflammation and steatohepatitis + loss of 10 % and more → can reduce fibrosis by at least one stage and induce histological resolution of NASH in 45 to 90 % of cases depending on studies + Mediterranean diet (fruits + vegetables + olive oil + fatty fish + legumes + whole grains) → best-validated nutritional approach in NAFLD + reduction of simple sugars (fructose + sweetened beverages) particularly important as de novo lipogenesis is stimulated by fructose
- Physical activity : 150 to 300 minutes per week of moderate-intensity aerobic activity (brisk walking + cycling + swimming) + resistance training (weight training) → independently reduce hepatic steatosis and improve insulin resistance even without significant weight loss + regular physical activity is beneficial independently of its weight impact on liver histology
- Optimizing the treatment of type 2 diabetes : pioglitazone (thiazolidinedione) → histological improvement of NASH with fibrosis in diabetic and non-diabetic patients (level 1 evidence) + GLP-1 receptor agonists (semaglutide 2,4 mg weekly + liraglutide) → histological resolution of NASH in 40-60 % of cases in clinical trials (LEAN + SEMINAL + ESSENCE) + reduction of one stage of fibrosis in phase 3 trials + SGLT-2 inhibitors (empagliflozin + dapagliflozin) → reduce hepatic steatosis measured by MRI-PDFF + these drugs are the preferred choices in NAFLD patients with type 2 diabetes
- Resmétirom (Rezdiffra®) - the first specific drug approved for NASH: selective hepatic thyroid hormone receptor beta (THRβ) agonist → stimulates mitochondrial beta-oxidation of fatty acids and reduces de novo lipogenesis without cardiovascular or bone effects of systemic thyroid hormones + approved by FDA in March 2024 for NASH/MASH with moderate to advanced fibrosis (F2-F3) in adults + MAESTRO-NASH trial: resolution of NASH without worsening fibrosis in 29 % vs. 10 % placebo + reduction of one fibrosis stage in 26 % vs. 14 % + not yet approved by Health Canada at time of writing
- Bariatric surgery and next-generation GLP-1 agonists: sleeve gastrectomy and Roux-en-Y gastric bypass → most effective treatment of NAFLD associated with morbid obesity → histological resolution of NASH in 80 to 90 % + regression of fibrosis in 40 to 50 % of cases + tirzepatide (dual GIP/GLP-1 agonist) → weight losses of 20 to 22 % with very high rates of histological resolution of NASH in phase 3 trials (SURMOUNT-NASH)
- Monitoring HCC and cirrhosis: confirmed F3-F4 fibrosis → biannual liver ultrasound ± AFP to screen for HCC + cirrhosis → upper GI endoscopy (EOGD) to screen for esophageal varices at diagnosis then according to results + specialized hepatological follow-up every 6 to 12 months + screening for metabolic comorbidities annually
- Cofactors to be corrected : abstinence or minimal alcohol consumption (even light alcohol consumption aggravates steatosis and fibrosis in NAFLD) + avoidance of steatogenic drugs (amiodarone + tamoxifen + long-term corticosteroids + methotrexate + valproate) if possible + vaccination against hepatitis A and B if no acquired immunity + treatment of obstructive sleep apnea if present (OSA aggravates NAFLD through intermittent hypoxia)
Situations requiring urgent medical assessment
Any patient with known or suspected NAFLD presenting jaundice (icterus) + severe abdominal pain + rapid increase in abdominal circumference with edema of the lower limbs (ascites) + vomiting of blood or black stools (oesophageal variceal haemorrhage) + confusion or disorientation (hepatic encephalopathy) + or sudden and rapidly worsening asthenia should seek urgent medical advice. disorientation (hepatic encephalopathy) + or sudden and rapidly worsening asthenia should seek urgent medical attention - these signs may indicate decompensation of cirrhosis (acute liver failure + variceal haemorrhage + encephalopathy) requiring immediate hospital care.
For an initial evaluation of NAFLD, prescription of FIB-4, referral to liver elastography (FibroScan®) or to a gastroenterologist-hepatologist, Clinique Omicron offers medical consultations at its points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's specialized physicians and nurse practitioners (NPNs) support patients with non-alcoholic fatty liver disease in the initial assessment of fibrosis risk (FIB-4 calculation + complete metabolic workup), referral to hepatic elastography (FibroScan®) and specialized hepatology teams, implementation of lifestyle modifications and optimization of treatment of metabolic comorbidities (type 2 diabetes + dyslipidemia + obesity). Consultations are available at several points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a physician or gastroenterologist/hepatologist. NAFLD/MASLD with advanced fibrosis (F3-F4) requires specialized hepatology follow-up to monitor complications (hepatocellular carcinoma + varices + liver failure) and evaluate new therapies.
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