What are the diagnostic criteria (elevated waist circumference, high triglycerides, low HDL cholesterol, hypertension, impaired fasting glucose) for metabolic syndrome, the criteria for non‑alcoholic fatty liver disease (hepatic steatosis without significant alcohol intake) and alcoholic liver disease (excessive alcohol consumption with AST/ALT ratio >2), and what evidence‑based management steps should be followed for each, presented as an algorithm?

Diagnostic Criteria and Management of Metabolic Syndrome, NAFLD, and Alcoholic Liver Disease

Metabolic Syndrome Diagnostic Criteria

Metabolic syndrome requires the presence of at least 2 metabolic risk factors from the following: central obesity (ethnicity-specific waist circumference cutoffs), elevated triglycerides ≥150 mg/dL or treatment for hypertriglyceridemia, reduced HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women) or treatment, hypertension (systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg) or treatment, and elevated fasting plasma glucose (100-125 mg/dL for prediabetes) or HbA1c ≥48 mmol/mol (6.5%) for diabetes. 1

• The presence of metabolic syndrome strongly predicts steatohepatitis in patients with NAFLD and serves as a clinical marker for those at risk of underlying NASH and progressive fibrosis 1
• Patients with NAFLD should undergo annual screening for diabetes using HbA1c, as they represent a high-risk group for type 2 diabetes 1
• Cardiovascular disease is the most common cause of death in patients with NAFLD, making aggressive management of metabolic risk factors essential 1

NAFLD Diagnostic Criteria

The diagnosis of NAFLD requires four elements: (1) hepatic steatosis by imaging (>5% hepatocytes) or histology (>5.6% proton density fat fraction by MRS/MRI), (2) alcohol consumption below significant thresholds (≤21 drinks/week in men, ≤14 drinks/week in women), (3) exclusion of competing etiologies for steatosis, and (4) exclusion of co-existing chronic liver diseases. 1

Alcohol Consumption Thresholds

• The European definition uses ≥30 g/day for men and ≥20 g/day for women as the upper limit for NAFLD diagnosis 1
• The American definition uses 21 drinks per week (average) in men and 14 drinks per week (average) in women over a 2-year period 1
• When self-reported alcohol consumption is inconsistent with clinical suspicion, confirmation with family members or close friends should be obtained 1
• Use validated questionnaires (AUDIT-C) to quantify alcohol consumption and consider biomarkers (urine ethyl glucuronide, blood phosphatidylethanol) when history is unreliable 2

Exclusion of Competing Etiologies

• Rule out hepatitis C (especially genotype 3), medications (antiarrhythmics, anticonvulsants, antiretrovirals, hormone modulators), Wilson's disease, hemochromatosis, autoimmune liver disease, and severe malnutrition 1, 2
• Obtain comprehensive laboratory evaluation: viral serology, autoimmune markers (ANA, ASMA), iron studies (ferritin, transferrin saturation), copper studies, alpha-1 antitrypsin level, and thyroid function tests 1, 2
• Elevated ferritin with transferrin saturation elevation requires HFE gene testing; homozygote or compound heterozygote C282Y mutations may warrant liver biopsy 1
• Elevated autoantibodies (ANA >1:160 or ASMA >1:40) occur in 21% of NAFLD patients and are generally epiphenomena unless accompanied by very high aminotransferases and high globulin 1

Alcoholic Liver Disease Diagnostic Criteria

Alcoholic liver disease is diagnosed when alcohol consumption exceeds 30 g/day (approximately 2 drinks) in men or 20 g/day in women, with hepatic steatosis and characteristic features including AST/ALT ratio >2 (though this ratio is not required for diagnosis). 1

• The relationship between alcohol and liver injury depends on beverage type, drinking patterns, duration of exposure, and individual/genetic susceptibility, making quantitative thresholds somewhat arbitrary 1
• Patients consuming moderate amounts of alcohol (20-50 g/day in women, 30-60 g/day in men) with metabolic risk factors represent an overlapping condition termed MetALD (Metabolic Dysfunction and Alcohol-Related Liver Disease) 3
• The overall impact of metabolic risk factors on steatosis occurrence appears higher than alcohol in patients with moderate consumption 1

Risk Stratification Algorithm for NAFLD

Step 1: Identify High-Risk Patients Requiring Screening

Screen the following three groups for clinically significant fibrosis (F2 or higher): 1

1. All patients with type 2 diabetes (20% have clinically significant fibrosis) 1
2. Patients with 2 or more metabolic risk factors (stepwise increase in cirrhosis/HCC risk with each additional trait) 1
3. Patients with incidental hepatic steatosis on imaging, especially with elevated aminotransferases (11% at high risk for advanced fibrosis) 1

Step 2: Initial Laboratory Assessment

• Obtain comprehensive metabolic panel, complete blood count, lipid panel, HbA1c, and quantitative alcohol history 1
• Exclude competing etiologies with viral serology, autoimmune markers, iron studies, and other tests as indicated 1, 2

Step 3: Non-Invasive Fibrosis Assessment

Calculate NAFLD Fibrosis Score (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio) for all at-risk patients: 1

• Score <-1.455: 90% sensitivity to exclude advanced fibrosis (F3-F4); reassess in 2-3 years 1
• Score >0.676: 67% sensitivity and 97% specificity for advanced fibrosis; proceed to Step 4 1
• Indeterminate scores (-1.455 to 0.676): Consider Enhanced Liver Fibrosis (ELF) panel or transient elastography 1

Step 4: Liver Biopsy Indications

Obtain liver biopsy in the following scenarios: 1

• NAFLD Fibrosis Score >0.676 or other non-invasive tests suggesting F2 or higher fibrosis 1
• Presence of metabolic syndrome with persistently abnormal liver biochemistries 1
• Competing etiologies or co-existing chronic liver diseases cannot be excluded without biopsy 1
• Elevated ferritin with homozygote/compound heterozygote C282Y HFE mutations 1

Do NOT perform liver biopsy in: 1

• Asymptomatic patients with incidental steatosis on imaging who have normal liver biochemistries 1

Management of NAFLD/NASH

Lifestyle Modifications (First-Line for All Patients)

Weight Loss Targets: 1

• 3-5% body weight loss: Improves steatosis 1
• 7-10% body weight loss: Required to improve necroinflammation and fibrosis 1
• Achieve through calorie deficit with reduction of refined carbohydrates and processed foods, increased vegetables, lean protein, and fish 1

Physical Activity: 1

• 150-300 minutes per week of moderate-intensity aerobic exercise over minimum 3 days per week 1
• Resistance exercise at least 2 days per week (lower cardiorespiratory demand, suitable for patients with poor baseline fitness) 1
• Both aerobic and resistance training reduce liver fat independent of weight loss 1

Alcohol Consumption: 1

• Patients with cirrhosis: Abstinence strongly recommended 1
• Patients with pre-cirrhotic NAFLD: Minimize or abstain, as alcohol accelerates disease progression 1
• Reassess alcohol consumption at regular intervals, as consumption fluctuates over time 1

Smoking Cessation: 1

• All patients should be asked about smoking history and offered smoking cessation services 1

Metabolic Risk Factor Management

Diabetes Management: 1

• Screen annually with HbA1c in all NAFLD patients 1
• Optimize glycemic control with insulin-sensitizing agents when appropriate 1

Dyslipidemia Management: 1

• Treat proatherogenic dyslipidemia (high triglycerides, low HDL, small dense LDL) with statins as indicated 1
• Statins are safe in NAFLD and reduce cardiovascular mortality 1

Hypertension Management: 1

• Target blood pressure <130/85 mm Hg 1
• Uncontrolled hypertension is a major risk for all-cause and CVD-related mortality 1

Pharmacological Therapy for NASH

Resmetirom has been recently approved for non-cirrhotic NASH with significant fibrosis (F2-F3) 3

Pioglitazone may be considered in patients with biopsy-proven NASH, particularly those with type 2 diabetes or prediabetes (based on intensive lifestyle interventions being cost-effective in F2 or higher) 1

Surveillance and Monitoring

Patients with F0-F1 fibrosis: 3

• Minimal risk of progression to cirrhosis 3
• Focus on lifestyle modifications and metabolic risk factor management 1

Patients with F2 or higher fibrosis: 1, 3

• Increased risk of progression requiring targeted interventions 1, 3
• Consider enrollment in clinical trials for emerging therapies 1

Patients with F3-F4 fibrosis: 3

• Independent risk factor for liver-related and non-liver-related mortality 3
• Hepatocellular carcinoma surveillance as indicated 3

Management of Alcoholic Liver Disease

Alcohol Abstinence: 1

• Continued drinking is the strongest risk factor for decompensation, exceeding any histological or laboratory parameters 1
• Abstinence dramatically reduces age-specific mortality rates 1
• Refer to smoking cessation services and alcohol treatment programs 1

Nutritional Support:

• Address severe malnutrition common in alcoholic liver disease 1

Management of Complications:

• Both alcohol use and obesity correlate with progression of portal hypertension in chronic liver disease 1
• Manage decompensated cirrhosis complications (ascites, variceal bleeding, hepatic encephalopathy) according to standard protocols

Metabolic Risk Factor Management:

• Address coexisting metabolic conditions, as alcohol and metabolic factors interact synergistically to accelerate liver disease progression 1

Common Pitfalls to Avoid

• Failing to quantitatively assess alcohol consumption leads to misclassification between NAFLD and ALD; always use validated questionnaires and consider biomarkers when history is unreliable 3, 2
• Not recognizing MetALD (overlap between metabolic risk factors and moderate alcohol consumption) results in inappropriate management 3
• Relying solely on liver enzymes for diagnosis, as aminotransferases may be normal despite significant disease 3
• Overlooking competing etiologies (medications, viral hepatitis, genetic disorders) leads to missed diagnoses requiring different management 3, 2
• Assuming elevated ferritin indicates hemochromatosis without checking transferrin saturation and HFE gene testing, as mildly elevated ferritin is common in NAFLD 1