Liver Function Tests (LFTs)

Summary

Liver function tests (LFTs) are a panel of blood tests commonly used to evaluate liver health and function. The tests include enzymes that indicate hepatocellular damage (ALT and AST), markers of cholestasis (ALP, GGT, and bilirubin), and parameters of synthetic function (albumin and PT/INR). Understanding the pattern of LFT abnormalities helps identify whether liver injury is primarily hepatocellular, cholestatic, or mixed. This systematic approach, combined with clinical context, guides further investigation and management of liver disease.

Overview

• Liver function tests (LFTs) are among the most frequently ordered blood tests in clinical practice
• Standard LFT panel includes:
  • Hepatocellular markers: ALT (alanine aminotransferase), AST (aspartate aminotransferase)
  • Cholestatic markers: ALP (alkaline phosphatase), GGT (gamma-glutamyltransferase), bilirubin
  • Synthetic function: Albumin, PT/INR
• LFTs are requested for multiple reasons:
  • Screening in asymptomatic patients
  • Investigation of suspected liver disease
  • Monitoring known liver disease
  • Assessing hepatotoxic medication effects

Hepatocellular Pattern of Injury

Hepatocellular injury is characterized by predominant elevation of aminotransferases (ALT and AST), indicating damage to hepatocytes with enzyme leakage into the bloodstream.

ALT and AST

• ALT (Alanine aminotransferase)
  • More specific to liver (found primarily in hepatocyte cytoplasm)
  • Normal range: 3-40 IU/L
• AST (Aspartate aminotransferase)
  • Found in liver, heart, skeletal muscle, kidneys, and erythrocytes
  • Present in both cytoplasm and mitochondria of hepatocytes
  • Normal range: 3-30 IU/L

AST:ALT Ratio

• AST:ALT < 1 (ALT > AST):
  • Viral hepatitis
  • MASLD (metabolic dysfunction-associated steatotic liver disease)
  • Drug-induced liver injury
  • Extrahepatic cholestasis
• AST:ALT ≥ 2: Classic for alcoholic liver disease
  • Alcohol-associated hepatitis (AST usually < 400 U/L)
  • Advanced cirrhosis
  • Muscle damage
  • Myocardial infarction

Degree of Elevation

Cholestatic Pattern of Injury

Cholestasis refers to impaired bile flow, characterized by predominant elevation of ALP and GGT, often with elevated bilirubin.

Alkaline Phosphatase (ALP)

• Enzyme found in biliary epithelial cells, bone, placenta, and intestine
• Normal range: 30-100 IU/L
• Elevated in:
  • Biliary obstruction (intrahepatic or extrahepatic)
  • Infiltrative liver diseases
  • Bone disease (Paget's, metastases)
  • Pregnancy (3rd trimester)

Gamma-glutamyltransferase (GGT)

• Found in hepatocytes and biliary epithelial cells
• Normal range: 8-60 IU/L
• Most sensitive marker for liver disease
• Helps confirm hepatic origin of elevated ALP
• Isolated elevation classically associated with alcohol excess

Common Causes of Cholestasis

Bilirubin

• Normal range: 3-17 μmol/L
• Jaundice typically visible when bilirubin > 50 μmol/L
• Can be fractionated into:
  • Unconjugated (indirect): Water-insoluble
  • Conjugated (direct): Water-soluble

Patterns of Hyperbilirubinemia

• Predominantly unconjugated:
  • Hemolysis
  • Gilbert syndrome
  • Crigler-Najjar syndrome
• Predominantly conjugated:
  • Biliary obstruction
  • Hepatocellular injury
  • Dubin-Johnson syndrome
  • Rotor syndrome

Hepatic Synthetic Function

True markers of liver function assess the liver's ability to synthesize proteins and maintain homeostasis.

Albumin

• Normal range: 35-50 g/L
• Exclusively produced by the liver
• Half-life: ~20 days (reflects chronic liver dysfunction)
• Decreased in:
  • Chronic liver disease/cirrhosis
  • Malnutrition
  • Nephrotic syndrome
  • Protein-losing enteropathy

Prothrombin Time (PT/INR)

• Assesses clotting factors I, II, V, VII, IX, X (vitamin K-dependent)
• Short half-life of factors (especially factor VII: 4-6 hours)
• More sensitive for acute liver dysfunction than albumin
• Elevated PT/INR indicates:
  • Severe acute liver injury
  • Advanced chronic liver disease
  • Vitamin K deficiency (differentiate with vitamin K trial)

Systematic Approach to LFT Interpretation

Step 1: Determine the Pattern

• Hepatocellular: ALT/AST elevation > ALP elevation
• Cholestatic: ALP elevation > ALT/AST elevation
• Mixed: Both significantly elevated

R Value Calculation

R = (ALT ÷ ULN) / (ALP ÷ ULN)

• R ≥ 5: Hepatocellular pattern
• R ≤ 2: Cholestatic pattern
• R 2-5: Mixed pattern

Step 2: Assess Severity

• Check bilirubin (marker of severity)
• Evaluate synthetic function (albumin, PT/INR)
• Consider degree of enzyme elevation

Step 3: Clinical Context

• Duration of abnormalities
• Associated symptoms
• Risk factors (alcohol, medications, metabolic syndrome)
• Physical examination findings

Further Investigations

For Hepatocellular Pattern

• Viral serologies: Hepatitis A, B, C
• Autoimmune markers:
  • ANA (anti-nuclear antibody)
  • ASMA (anti-smooth muscle antibody)
  • Anti-LKM (liver/kidney microsomal antibody)
  • Immunoglobulins (IgG elevation in autoimmune hepatitis)
• Metabolic tests:
  • Ferritin, transferrin saturation (hemochromatosis)
  • Ceruloplasmin, 24-hour urine copper (Wilson disease)
  • Alpha-1 antitrypsin levels
• Imaging: Ultrasound to assess liver structure

For Cholestatic Pattern

• First-line: Abdominal ultrasound
  • Dilated ducts → extrahepatic obstruction
  • Normal ducts → intrahepatic cholestasis
• Further imaging:
  • MRCP for biliary tree visualization
  • CT for pancreatic masses
• Autoimmune markers:
  • AMA (anti-mitochondrial antibody) - specific for PBC
  • p-ANCA - associated with PSC

Summary