What can cause elevated Liver Function Tests (LFTs) in a non-alcoholic patient?

Causes of Elevated Liver Function Tests in Non-Alcoholic Patients

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated LFTs in non-drinkers, accounting for approximately 26% of incidental LFT abnormalities in primary care settings and affecting 20-30% of the general population. 1

Primary Differential Diagnosis Framework

When evaluating elevated LFTs without alcohol consumption, systematically exclude competing etiologies in this order:

Most Common Causes (Address First)

• Non-alcoholic fatty liver disease (NAFLD): The leading cause in developed countries, with prevalence increasing to 70% with obesity and 90% with diabetes mellitus 2, 1

  • Typically presents with mild aminotransferase elevations (<5 times upper limit) 1
  • AST:ALT ratio typically <1 (distinguishes from alcoholic liver disease where ratio is >2) 1, 3
  • Associated with metabolic risk factors: obesity, type 2 diabetes, insulin resistance, metabolic syndrome 1

• Chronic viral hepatitis: Hepatitis B and C must be excluded through serological testing 4

  • Can present with normal or mildly elevated LFTs 4
  • Serology is the key early diagnostic test 4

• Drug-induced liver injury: Obtain detailed medication history including over-the-counter drugs, supplements, and herbal products 4

Less Common but Treatable Causes (Must Exclude)

• Hemochromatosis: Test serum ferritin and transferrin saturation 4

  • Mildly elevated ferritin is common in NAFLD and does not necessarily indicate iron overload 4
  • If ferritin elevated with high transferrin saturation, test for HFE gene mutations 4
  • Consider liver biopsy if homozygote or compound heterozygote C282Y mutation present 4

• Autoimmune liver disease: Check antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) 4

  • Low titers (ANA ≤1:160 or ASMA ≤1:40) are common in NAFLD and generally clinically insignificant 4
  • High titers with very elevated aminotransferases and elevated globulin warrant complete autoimmune workup 4

• Wilson's disease: Consider in patients under age 40 with unexplained liver disease 4

• Alpha-1 antitrypsin deficiency: Screen with serum alpha-1 antitrypsin level and phenotype 4

Rare Extrahepatic Causes

• Endocrine disorders: Addison's disease can cause elevated liver enzymes with hyponatremia and hyperkalemia 5

  • Fully reversible with appropriate hormone replacement 5

• Systemic diseases: Sarcoidosis and other systemic conditions may involve the liver 6, 7

Critical Clinical Pitfalls to Avoid

Do not assume the magnitude of LFT elevation correlates with disease severity or prognosis. 4, 1

• Patients with significant liver fibrosis may have normal or minimally elevated liver enzymes 4, 1
• The most common causes of chronic liver disease (NAFLD, alcohol-related disease, hepatitis C) frequently present with only mild-to-moderate abnormalities 4

Do not rely on "normal" LFTs to exclude significant liver disease. 4, 1

• Many patients with advanced fibrosis have liver enzymes within the normal reference range 4
• Current upper limits of normal for ALT may be too high due to inclusion of patients with occult NAFLD in reference populations 4

Recommended Diagnostic Approach

Initial Workup (All Patients)

1. Detailed history: 4

   • Alcohol consumption (quantify precisely: >21 drinks/week in men or >14 drinks/week in women suggests alcoholic etiology) 4
   • All medications, supplements, herbal products 4
   • Metabolic risk factors: obesity, diabetes, hypertension, dyslipidemia 4
   • Family history of liver disease 4

2. Laboratory testing: 4

   • Hepatitis B surface antigen, hepatitis C antibody
   • Serum ferritin and transferrin saturation
   • ANA and ASMA
   • Fasting glucose and hemoglobin A1c
   • Lipid panel
   • Consider: ceruloplasmin (if age <40), alpha-1 antitrypsin level and phenotype

3. Imaging: 4

   • Abdominal ultrasound to assess for steatosis and exclude structural abnormalities
   • Note: Ultrasound detects steatosis but does not assess fibrosis stage 1

Risk Stratification for NAFLD Patients

For confirmed or suspected NAFLD, calculate non-invasive fibrosis scores to identify patients at risk for advanced fibrosis: 1

• FIB-4 score: Low risk if <1.3 2
• NAFLD Fibrosis Score: Low risk if ≤-1.455 2

Screen for metabolic comorbidities in all NAFLD patients: 4

• Type 2 diabetes screening
• Cardiovascular disease risk assessment
• Metabolic syndrome evaluation

When to Consider Liver Biopsy

• Persistently high ferritin with elevated transferrin saturation and HFE mutations 4
• High autoantibody titers with features suggesting autoimmune disease 4
• Uncertain diagnosis after non-invasive workup 4
• NAFLD patients with intermediate or high risk on non-invasive fibrosis scores 1

Pattern Recognition for Specific Etiologies

NAFLD pattern: 1

• AST:ALT ratio <1
• Mild aminotransferase elevations
• Presence of metabolic risk factors

Alcoholic liver disease pattern (if history unclear): 1, 3

• AST:ALT ratio >2 (ratios >3 highly specific)
• Elevated GGT
• Consider additional biomarkers if suspicion remains

Cholestatic pattern in NAFLD: 8

• Patients with predominantly elevated alkaline phosphatase have higher risk of advanced fibrosis (31.3% vs 4.5% in mixed pattern) 8
• Also associated with higher prevalence of diabetes, hypertension, and hypertriglyceridemia 8