What is a liver function test (LFT) and how is it used to diagnose and manage liver disease?

Liver Function Tests: Comprehensive Overview and Clinical Application

Liver function tests (LFTs) are biochemical blood tests that provide critical information about liver health, disease progression, and treatment efficacy, but when used in isolation, they are neither specific diagnostic tools nor specific exclusion tools for liver disease. 1

Components of Standard Liver Blood Test Panel

Hepatobiliary Enzymes (Markers of Liver Injury)

• Aspartate aminotransferase (AST): Released when liver cells are damaged
• Alanine aminotransferase (ALT): More specific to liver damage than AST
• Alkaline phosphatase (ALP): Elevated in cholestatic conditions
• Gamma-glutamyl transferase (GGT): Used to determine if ALP elevation is of hepatic origin

Markers of Liver Function

• Bilirubin: Breakdown product of hemoglobin
  • Total bilirubin: Comprises both conjugated and unconjugated fractions
  • Direct (conjugated) bilirubin: Indicates parenchymal liver disease or biliary obstruction
  • Indirect (unconjugated) bilirubin: Elevated in hemolysis or impaired conjugation
• Albumin: Protein produced only by the liver; marker of synthetic function
• Prothrombin time (PT)/International Normalized Ratio (INR): Assess blood clotting; indicate liver's ability to produce clotting factors

Additional Parameters

• Platelet count: Decreased in advanced liver disease (thrombocytopenia)
• Complete blood count: May indicate anemia or infection

Clinical Significance and Interpretation

Patterns of Abnormality

1. Hepatocellular Pattern (predominant elevation of AST/ALT):

   • Viral hepatitis
   • Alcoholic liver disease
   • Non-alcoholic fatty liver disease (NAFLD)
   • Drug-induced liver injury
   • Autoimmune hepatitis

2. Cholestatic Pattern (predominant elevation of ALP/GGT):

   • Biliary obstruction
   • Primary biliary cholangitis
   • Primary sclerosing cholangitis
   • Drug-induced cholestasis

3. Mixed Pattern (elevation of both transaminases and cholestatic enzymes):

   • Some drug reactions
   • Alcoholic hepatitis
   • Malignant infiltration

Limitations of Liver Blood Tests

• LFTs alone cannot determine the specific cause of liver disease
• Normal LFTs do not exclude significant liver disease
• The degree of LFT abnormality does not always correlate with disease severity
• In fatty liver disease, enzymes may be normal or elevated, but the degree of abnormality is not related to progression from simple fatty liver to cirrhosis 1

Diagnostic Algorithm for Abnormal Liver Tests

Step 1: Confirm Abnormality

• Repeat testing in 1-2 weeks for elevated liver tests 2
• Consider physiological or non-hepatic causes of abnormal results

Step 2: Evaluate Pattern of Abnormality

• Determine if pattern is hepatocellular, cholestatic, or mixed
• Calculate R factor = (ALT/ALT upper limit of normal) ÷ (ALP/ALP upper limit of normal)
  • R > 5: Hepatocellular
  • R < 2: Cholestatic
  • R = 2-5: Mixed

Step 3: Initial Workup Based on Pattern

• For all patterns:

  • Hepatitis B serology (HBsAg, anti-HBc)
  • Hepatitis C antibody (with reflex RNA testing if positive)
  • HIV testing if risk factors present
  • Abdominal ultrasound 2

• For hepatocellular pattern:

  • Alcohol history
  • Medication review
  • Autoimmune markers (ANA, SMA, IgG levels)
  • Iron studies (ferritin, transferrin saturation)
  • Ceruloplasmin (if age <40 years)

• For cholestatic pattern:

  • Confirm hepatic origin of ALP with GGT
  • Abdominal imaging to assess biliary system
  • Consider antimitochondrial antibodies (AMA)
  • Review medications

Step 4: Monitoring and Management

• For mild elevations (<5× ULN): Monitor every 1-3 months

• For moderate elevations: Monitor every 2-3 weeks

• For severe elevations: Monitor 2-3 times weekly 2

• Indications for expedited evaluation or hepatology referral:

  • ALT/AST >5× ULN
  • ALT/AST >3× ULN with total bilirubin ≥2× ULN
  • Persistent elevation >6 months despite interventions
  • Development of symptoms (jaundice, abdominal pain, fatigue)
  • Signs of hepatic decompensation 2

Special Considerations

Gilbert's Syndrome

• Most common cause of isolated elevated bilirubin
• Inherited disorder with impaired bilirubin conjugation
• Benign condition requiring reassurance only 1

Drug-Induced Liver Injury

• Withhold potentially hepatotoxic medications
• Liver function typically normalizes within 2-7 weeks after discontinuation 2
• Consider alternative causes if abnormalities persist

Pediatric Considerations

• In neonates and infants with conjugated bilirubin >25 μmol/L, urgent referral to a pediatrician is essential 1
• Physiological increase in unconjugated bilirubin may occur in neonatal period

Common Pitfalls in LFT Interpretation

• Overreliance on normal values: The ALFIE study showed that only 3.9% of patients with abnormal liver values were diagnosed with significant liver disease within 5 years 1
• Misinterpreting albumin levels: Low albumin can be caused by non-hepatic conditions (sepsis, malnutrition, nephrotic syndrome)
• Failure to recognize non-hepatic sources of enzyme elevation: ALP can be elevated in bone disease; AST can be elevated in muscle injury
• Not considering medication effects: Many medications can cause transient LFT abnormalities
• Missing subclinical liver disease: Liver disease can develop silently with no symptoms until complications of liver failure or portal hypertension develop 1

Lifestyle Modifications for Patients with Abnormal LFTs

• Mediterranean diet
• Regular exercise
• Weight loss if overweight/obese
• Alcohol cessation if applicable 2

By understanding the components, patterns, and limitations of liver function tests, clinicians can more effectively diagnose and manage liver diseases, improving patient outcomes through early intervention and appropriate referral.