What is the likely cause and appropriate work‑up for an obese patient with elevated liver enzymes and a normal liver ultrasound?

Obese Patient with Elevated Liver Enzymes and Normal Ultrasound

Most Likely Diagnosis

Non-alcoholic fatty liver disease (NAFLD) is the most likely diagnosis, as ultrasound has poor sensitivity (53-65%) for detecting mild hepatic steatosis and 83% of patients with negative ultrasound may still have histologic steatosis. 1

The normal ultrasound does not exclude NAFLD—it simply indicates that if steatosis is present, it is likely mild (<30% hepatic fat content). 1 Obesity is the strongest risk factor for NAFLD, increasing the risk of steatosis by a factor of approximately 15. 2

Initial Diagnostic Work-Up

Exclude Alternative Causes of Elevated Liver Enzymes

• Quantify alcohol consumption using detailed clinical evaluation, as excessive intake (>21 drinks/week in men, >14 drinks/week in women) defines alcoholic liver disease rather than NAFLD. 3

• Calculate the AST:ALT ratio to differentiate between alcoholic and non-alcoholic causes: a ratio >2 suggests alcohol-induced disease, while a ratio <1 indicates metabolic disease-related NAFLD. 4

• Exclude viral hepatitis (hepatitis B and C serology), drug-induced liver injury (medication review), hereditary hemochromatosis (ferritin and transferrin saturation), autoimmune hepatitis (ANA, ASMA, immunoglobulins), alpha-1-antitryphen deficiency, and Wilson disease (ceruloplasmin if age <40). 3, 4, 1

• Note that mildly elevated serum ferritin is common in NAFLD and does not necessarily indicate iron overload; only pursue genetic hemochromatosis testing if both ferritin and transferrin saturation are elevated. 3

Assess for Metabolic Syndrome Components

• Document body mass index and waist circumference, as NAFLD prevalence increases dramatically with obesity and central adiposity. 4, 1

• Obtain fasting glucose or HbA1c to screen for diabetes, as patients with type 2 diabetes should be screened for NAFLD regardless of liver enzyme levels. 1

• Check lipid panel (triglycerides, HDL cholesterol, LDL cholesterol) and blood pressure, as these metabolic syndrome components frequently coexist with NAFLD. 4, 1, 5

Risk Stratification for Advanced Fibrosis

Calculate FIB-4 score or NAFLD Fibrosis Score (NFS) to assess risk of advanced fibrosis, as liver enzyme levels alone cannot predict fibrosis stage or distinguish simple steatosis from steatohepatitis. 4, 1, 6 This is critical because 25-30% of NAFLD cases progress to NASH with inflammation and hepatocyte injury, which can lead to cirrhosis and hepatocellular carcinoma. 4

• FIB-4 uses age, AST, ALT, and platelet count and has the best diagnostic accuracy among simple non-invasive scores for identifying advanced fibrosis. 1

• High-risk patients (age >50 years, diabetes, metabolic syndrome) warrant particular attention to fibrosis assessment. 1

• If FIB-4 or NFS suggests intermediate or high risk of advanced fibrosis, consider referral to hepatology for further evaluation with transient elastography or possible liver biopsy. 1

Treatment Strategy

• Prescribe weight loss of 7-10% body weight through caloric restriction and exercise as the primary treatment, as this has been shown to improve liver enzymes and liver histology. 4, 7

• Recommend dietary modifications: restrict saturated fat to <7% of total calories, reduce processed foods and those high in added fructose, and consider a Mediterranean diet pattern. 4, 7

• Encourage physical activity including both aerobic exercise and resistance training, with a goal of at least 150 minutes per week of moderate-intensity activity. 7

• Statins are not contraindicated and may be beneficial for cardiovascular risk reduction in NAFLD patients with dyslipidemia. 4

Monitoring and Follow-Up

• Repeat liver enzymes in 2-3 months to establish trend, as 84% of abnormal liver tests remain abnormal at 1 month and 75% at 2 years. 4

• Reassess metabolic parameters (weight, BMI, glucose, lipids) every 3-6 months to monitor response to lifestyle interventions. 7

• Refer immediately if ALT >8× upper limit of normal (ULN) or >5× baseline, or if ALT >3× ULN with total bilirubin >2× ULN, or if evidence of synthetic dysfunction (low albumin, prolonged INR). 4

Critical Pitfalls to Avoid

• Do not assume the normal ultrasound excludes NAFLD—ultrasound has poor sensitivity for mild steatosis, and nearly half of patients with "mild" steatosis on ultrasound actually have moderate steatosis on definitive testing. 1

• Do not rely on liver enzyme levels to distinguish simple steatosis from NASH—transaminase concentrations cannot separate NAFL from NASH even with adjusted thresholds, and correlation coefficients between enzymes and histologic severity are only 0.33-0.40. 6

• Do not order CT scan as the primary diagnostic modality, as CT fails to detect early steatosis and lacks accuracy for mild disease; ultrasound remains the appropriate first-line imaging tool despite its limitations. 4

• Consider MRI if ultrasound visualization is inadequate (common in obese patients), as MRI is superior for detecting mild steatosis (<30% fat) and provides more accurate quantification of hepatic fat. 1