How to approach a patient with deranged liver function tests (LFTs) and suspected non-alcoholic fatty liver disease (NAFLD) or viral hepatitis?

Approach to Deranged Liver Function Tests with Suspected NAFLD or Viral Hepatitis

Do not simply repeat abnormal liver blood tests—instead, immediately obtain a thorough clinical history and targeted examination to determine the underlying cause, as 84% of abnormal liver enzymes remain abnormal at 1 month and 75% at 2 years, making repeat testing without investigation inefficient and costly. 1

Initial Clinical Assessment

The first step requires obtaining specific historical elements that directly inform the differential diagnosis 1:

• Age and ethnicity/country of birth to assess hepatitis B or C risk 1
• Metabolic syndrome features: central obesity, hypertension, diabetes/insulin resistance, and dyslipidemia (for NAFLD) 1
• Alcohol intake: current and past consumption in average units per week, consider AUDIT-C screening 1
• Drug history: prescribed medications, over-the-counter drugs, herbal supplements, injecting drug use, and illicit substances 1
• Specific symptoms: jaundice, abdominal pain, weight loss, pruritus 1
• Family history of liver disease 1
• Travel history and occupational exposures 1

Pattern Recognition and Severity Classification

Interpret the pattern of liver test abnormalities 2:

• Hepatocellular pattern: Predominant ALT/AST elevation (ALT is most specific for hepatic damage) 2

  • Mild: <5× upper limit of normal (ULN)
  • Moderate: 5-10× ULN
  • Severe: >1000 U/L (consider acute viral hepatitis A, E, or other causes) 1

• Cholestatic pattern: Elevated alkaline phosphatase ± GGT 2

• Mixed pattern: Both transaminases and alkaline phosphatase elevated 2

Critical caveat: The extent of liver blood test abnormality does not necessarily indicate clinical significance—many patients with significant fibrosis have normal or near-normal liver enzymes. 1 Normal ALT does not exclude advanced liver disease. 2

Adjusted ALT Thresholds for NAFLD Populations

Use lower ALT thresholds when evaluating for NAFLD, as current "normal" ranges likely include patients with occult NAFLD 1:

• Males: ALT >30 U/L is significant 1
• Females: ALT >19 U/L is significant 1

These lower thresholds are supported by hepatitis B treatment guidelines and recognition that standard ULN values are too high. 1

Initial Laboratory Workup

Beyond the basic liver panel, obtain 1, 2:

• For viral hepatitis screening: Hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis C antibody 1
• Complete blood count and metabolic panel 2
• Fasting lipid panel and glucose/HbA1c (for NAFLD assessment) 2
• Consider: Iron studies, autoimmune markers, ceruloplasmin (if age <40), alpha-1 antitrypsin level depending on clinical context 3

Risk Stratification for Fibrosis

This is the critical step that determines management pathway. For patients with NAFLD or after excluding other causes 1, 2:

First-line non-invasive fibrosis assessment:

Calculate FIB-4 score or NAFLD Fibrosis Score (NFS) 1, 2:

• Low risk of advanced fibrosis: FIB-4 <1.3 or NFS ≤-1.455 1

  • For patients >65 years: use FIB-4 <2.0 or NFS <-0.12 1

• Indeterminate or high risk: Proceed to second-line testing 1

Second-line assessment:

• Enhanced Liver Fibrosis (ELF) score or transient elastography (FibroScan/ARFI) 1, 2
• FibroScan >16 kPa indicates advanced fibrosis requiring specialist referral 1

Referral Criteria

Immediate referral required for 1:

• Unexplained clinical jaundice
• Suspicion of hepatic or biliary malignancy
• Features of cirrhosis or portal hypertension on imaging or blood tests 1
• FibroScan >16 kPa 1

Routine specialist referral/discussion for 1:

• Negative extended liver etiology screen with no NAFLD risk factors
• Evidence of advanced liver disease
• Persistent abnormalities after initial workup

Low threshold for pediatric referral, as adult causes are less common in children and the differential diagnosis is broader. 1

Management Based on Etiology

For NAFLD:

• Lifestyle modifications (weight loss, exercise) are the cornerstone of treatment 2
• Pharmacological treatment considered for advanced fibrosis or cirrhosis 2
• Regular monitoring with laboratory tests and imaging to assess progression 2

For viral hepatitis:

• Hepatitis B: Antiviral therapy if HBV DNA >2000 IU/mL with ALT >ULN 1
• Hepatitis C: Refer for direct-acting antiviral therapy
• Important: Screen for HBV reactivation risk if immunosuppression planned 1

For alcoholic liver disease:

• Complete alcohol abstinence is essential 2
• Risk stratification with FibroScan/ARFI elastography 1
• Consider transplant evaluation for severe disease 2

Common Pitfalls to Avoid

• Do not assume transient abnormality: Only repeat tests without investigation if there is high clinical suspicion of an acute, reversible insult 1
• Do not rely solely on ALT levels: Normal or mildly elevated ALT does not exclude advanced fibrosis, particularly in NAFLD 1, 4
• Do not overlook non-hepatic causes: Consider muscle injury (check CPK), thyroid disease, and medications 2, 3
• Do not delay fibrosis assessment: Early identification of advanced fibrosis changes management and prognosis 1