What is the management approach for a patient with rising Liver Function Tests (LFTs)?

Management of Rising Liver Function Tests

When faced with rising LFTs, immediately stop all potentially hepatotoxic medications if ALT/AST exceeds 5× the upper limit of normal (ULN), or if any elevation occurs with jaundice or elevated bilirubin, regardless of the absolute enzyme level. 1

Immediate Assessment and Pattern Recognition

Initial Laboratory Evaluation

• Obtain a complete panel including ALT, AST, alkaline phosphatase (ALP), GGT, total and direct bilirubin, albumin, and prothrombin time/INR to determine the pattern and severity of liver injury 2
• Classify the pattern as:
  • Hepatocellular (predominant ALT/AST elevation) 2
  • Cholestatic (predominant ALP/GGT elevation) 2
  • Mixed (features of both) 2

Severity Stratification

• Mild elevations: <5× ULN 2
• Moderate elevations: 5-10× ULN 2
• Severe elevations: >10× ULN 2
• Life-threatening: >20× ULN 2

Critical History and Examination

Essential History Components

• Review all medications including prescription drugs, over-the-counter medications, herbal supplements, and illicit drugs 3, 2
• Quantify alcohol intake using AUDIT-C scoring tool (>19 indicates dependency requiring referral) 3, 2
• Assess metabolic syndrome features: central obesity, hypertension, diabetes, dyslipidemia 3
• Identify risk factors for viral hepatitis: country of birth (strongest predictor), injecting drug use, travel history 3
• Document timing: when medications were started relative to LFT abnormalities 4
• Elicit specific symptoms: jaundice, abdominal pain, pruritus, weight loss, nausea 3

Physical Examination Priorities

• Calculate body mass index and assess for central obesity 3
• Examine for hepatosplenomegaly, ascites, and stigmata of chronic liver disease 3

Core Aetiology Screen

Standard Panel (Perform First)

• Hepatitis B surface antigen (HBsAg) 3
• Hepatitis C antibody (if positive, confirm with HCV RNA PCR) 3, 2
• Serum ferritin and transferrin saturation (>45% suggests haemochromatosis) 3
• Immunoglobulin G levels and autoantibodies (ANA, ASMA) for autoimmune hepatitis 3, 2
• Anti-mitochondrial antibody if cholestatic pattern present 3
• Fasting glucose and lipid panel for NAFLD risk assessment 2

Important caveat: An isolated elevated ferritin commonly reflects dysmetabolic iron overload syndrome in the setting of alcohol excess or NAFLD, not haemochromatosis 3

Pattern-Specific Additional Testing

For Hepatocellular Pattern:

• Anti-HAV IgM, anti-HBc IgM if acute presentation 2
• Calculate FIB-4 or NAFLD Fibrosis Score if metabolic risk factors present 3, 2
  • FIB-4 <1.3 indicates low risk of advanced fibrosis 3
  • For patients >65 years, use higher cut-off of <2.0 3

For Cholestatic Pattern:

• Confirm hepatic origin with GGT (if ALP elevated alone) 2
• Abdominal ultrasound to evaluate for biliary obstruction 2
• Consider PSC if history of inflammatory bowel disease or autoimmune conditions 3

Management Based on Severity

Mild Elevations (<5× ULN)

• Monitor liver enzymes weekly until normalization 1, 2
• Discontinue potentially hepatotoxic medications and alcohol 2
• Do not simply repeat the same tests hoping for normalization—this delays diagnosis and is not cost-effective 3

Moderate Elevations (5-10× ULN)

• Monitor liver enzymes every 2-3 days until stable or improving 1, 2
• For immune checkpoint inhibitor hepatotoxicity (Grade 2): hold treatment temporarily; if no improvement after 3-5 days, start prednisone 0.5-1 mg/kg/day 1, 2

Severe Elevations (>10× ULN)

• Monitor liver enzymes every 1-2 days 2
• For immune checkpoint inhibitor hepatotoxicity (Grade 3): permanently discontinue treatment and immediately start methylprednisolone 1-2 mg/kg 1, 2
• Stop all hepatotoxic drugs immediately regardless of suspected causality 1

Life-Threatening Elevations (>20× ULN)

• Immediate hospitalization for intensive monitoring and supportive care 2
• Consider acute causes: hepatitis A, hepatitis E, cytomegalovirus, drug-induced liver injury 3

Critical Action Thresholds

Stop all potentially hepatotoxic drugs immediately if:

• ALT/AST >5× ULN 1
• Any elevation with jaundice 1
• Any elevation with elevated bilirubin in pre-existing liver disease 1

Continue monitoring until liver function returns to normal before considering rechallenge 1

Common Pitfalls to Avoid

• Do not assume normal ALT excludes significant liver disease—many patients with NAFLD, hepatitis C, or advanced fibrosis have normal or minimally elevated enzymes 1
• Do not continue hepatotoxic drugs with close monitoring when enzymes are >5× ULN—stop immediately 1
• Do not ignore the country of origin when assessing viral hepatitis risk—it is the strongest predictor, not ethnic group 3
• Do not overlook muscle injury as a source of elevated AST—obtain creatine kinase if suspected 3

Referral Indications

Refer to hepatology for:

• Hepatitis B (HBsAg positive) or hepatitis C (antibody and PCR positive) 3
• Autoimmune hepatitis (raised IgG with positive autoantibodies) 3
• Primary biliary cholangitis (cholestatic enzymes with positive anti-mitochondrial antibody) 3
• PSC (cholestatic enzymes with inflammatory bowel disease history) 3
• Haemochromatosis (ferritin elevated with transferrin saturation >45%) 3
• Persistent unexplained elevations or evidence of advanced fibrosis 2
• ALT >5× ULN 2

Special Populations

Harmful Alcohol Drinkers

• For consumption >50 units/week (men) or >35 units/week (women): perform risk stratification with FibroScan/ARFI elastography 2
• ARFI >7.8 kPa indicates high risk requiring hepatology referral 3

Children

• Maintain low threshold for paediatric referral—the differential diagnosis is wider and common adult causes are less frequent 3
• Neonatal cholestasis (conjugated bilirubin >25 μmol/L) requires urgent specialist assessment 3

Patients on Immune Checkpoint Inhibitors

• Infliximab is contraindicated for checkpoint inhibitor-induced hepatitis 2
• Consider liver biopsy if steroid-refractory or if differential diagnoses would alter management 2