Liver Function Tests (LFTs) - Interpretation

The Standard LFT Panel

Step 1: Identify the Dominant Pattern

Pattern 1 - Hepatocellular (Parenchymal) Injury

• ALT is more liver-specific than AST
• ALP is normal or mildly elevated (<3× ULN)
• Bilirubin may be elevated (both fractions)
• Albumin and PT usually normal unless >80% liver destroyed

Pattern 2 - Cholestatic Pattern

• AST/ALT normal or mildly elevated (<3× ULN)
• Serum cholesterol increased (in chronic cholestasis)
• Pruritus may be present
• GGT confirms ALP is of hepatic origin (not bone)

Pattern 3 - Mixed Pattern

Step 2: Assess Hepatic Synthetic Function

Albumin

• Half-life = 15-20 days → marker of chronic hepatic dysfunction
• Low in cirrhosis, chronic hepatitis (when >80% parenchyma lost)
• NOT low in acute hepatitis (because liver is not substantially destroyed)
• Confounders: malnutrition, nephrotic syndrome, protein-losing enteropathy

Prothrombin Time (PT) / INR

• Half-life of factors = hours to days → marker of acute hepatic function
• Most sensitive test for acute hepatic failure
• All clotting factors (except Factor VIII) are made in the liver
• Prolonged PT not responding to vitamin K = severe hepatocellular disease
• Confounders: warfarin use, vitamin K deficiency

Step 3: Bilirubin Fractionation

Unconjugated (Indirect) Hyperbilirubinemia

• Urine: no bilirubin (unconjugated is not water-soluble)
• Gilbert syndrome: benign, isolated mild unconjugated hyperbilirubinemia

Conjugated (Direct) Hyperbilirubinemia

• Urine: bilirubinuria present (conjugated bilirubin is water-soluble)
• Conjugated hyperbilirubinemia = when >30% of total bilirubin is conjugated

Step 4: Classic Disease Patterns (Summary)

Step 5: Key Ancillary Tests

• GGT: Confirms hepatic origin of elevated ALP; elevated 2-3× ULN in heavy drinkers; elevated in 70% of chronic alcoholics; elevated by drugs (phenytoin, valproate, barbiturates, methotrexate, warfarin)
• 5'-Nucleotidase: Confirms biliary origin; highest in cholestatic conditions
• Ammonia: Elevated only when >80% of liver tissue is destroyed; important in hepatic encephalopathy; pre-analytical errors are common (must be chilled on ice, tested immediately - levels rise ~20% in first hour; hemolysis and smoking falsely elevate)
• LDH: Rises in hepatocyte necrosis but very non-specific; isolated ALP + LDH elevation suggests space-occupying lesion

Pitfalls to Remember

1. Normal LFTs don't exclude liver disease - cirrhosis can have near-normal transaminases
2. ALP may be elevated physiologically - childhood growth, pregnancy; separate reference ranges needed for children
3. Fasting matters - intestinal ALP can elevate total ALP by 30% for up to 12 hours post-meal (in Lewis-positive group B/O secretors)
4. AST is non-specific - elevated in MI, rhabdomyolysis, hemolysis; always compare with ALT
5. Albumin half-life is long - not useful for detecting acute liver failure
6. INR is best for acute synthetic function assessment (hours to days for clotting factor turnover)
7. Wilson's disease classically shows low ALP despite significant liver disease

The AST:ALT Ratio (De Ritis Ratio) - Full Interpretation Guide

Why the Ratio Exists: Biochemical Basis

Normal Reference Point

Clinical Scenarios in Detail

1. AST:ALT ≥ 2:1 - Alcoholic Liver Disease

1. Vitamin B6 (pyridoxal-5-phosphate) deficiency - ALT is more dependent on B6 as a cofactor than AST. Malnourished alcoholic patients are commonly B6-deficient, selectively suppressing ALT.
2. Direct mitochondrial injury by alcohol - Ethanol and acetaldehyde damage mitochondria, releasing the large mitochondrial pool of AST (which makes up ~80% of total cellular AST) into circulation disproportionately.

Important caveat: The ratio is useful but AST is rarely >300-400 U/L in alcoholic hepatitis - if you see AST/ALT in the thousands with a high ratio, think ischemia or acetaminophen, not alcohol.

2. AST:ALT >1 in Cirrhosis (Any Cause)

• Specificity for cirrhosis: 94-100%
• Sensitivity for cirrhosis: 44-75% (so it misses many cases)

3. AST:ALT >1 in Wilson Disease

Additional clue in Wilson: ALP is often paradoxically low or normal despite significant liver injury - a unique pattern not seen in other diseases.

4. Ratio <1 (ALT > AST) - Viral Hepatitis / NAFLD

5. Extrahepatic Causes of High AST:ALT Ratio

Time Course Matters: A Critical Point

Practical Algorithm: When You See an Abnormal Ratio

AST:ALT ratio abnormal
       |
       ├── Ratio >2:1
       │       ├── Alcohol history? → Alcoholic hepatitis/ALD (confirm with GGT, MCV, CDT)
       │       ├── No alcohol + young patient? → Consider Wilson disease (check ceruloplasmin, ALP often low)
       │       └── Background chronic liver disease? → Cirrhosis (high specificity, check imaging/fibroscan)
       │
       ├── Ratio >1 but <2
       │       ├── Muscle involvement? → Check CK, aldolase
       │       ├── Cardiac? → Troponin, ECG
       │       ├── Thyroid? → TSH
       │       └── Early cirrhosis? → Reassess if chronic liver disease known
       │
       └── Ratio <1 (ALT>AST) - expected pattern
               ├── Acute viral hepatitis
               ├── NAFLD/MASLD
               ├── Drug-induced (non-alcoholic)
               └── Autoimmune hepatitis

Limitations to Remember

1. The ratio alone cannot diagnose ALD - must be interpreted with history, GGT, CDT (carbohydrate-deficient transferrin), MCV
2. Absolute levels matter too - very high ratios with low absolute values (e.g. AST 60, ALT 20) are less meaningful than moderate ratios with high values
3. Hemolysis falsely elevates AST (AST is present in RBCs) without affecting ALT
4. Strenuous exercise can elevate AST alone, creating a false high ratio
5. The ratio does not reflect disease severity - it only suggests etiology