Work-Up for Elevated Liver Function Tests
Do not simply repeat the same liver panel—instead, immediately obtain a thorough clinical history, perform a targeted physical examination, and order a core liver aetiology screen to identify the underlying cause. 1
Initial Clinical Assessment
When liver function tests are abnormal, 84% remain abnormal at 1 month and 75% at 2 years, making it inappropriate to simply recheck without investigating the cause unless there is high clinical suspicion for a transient process. 1
Essential History Elements
Obtain the following specific details 1:
- Age and ethnicity/country of birth (to assess hepatitis B or C risk)
- Specific symptoms: jaundice, right upper quadrant pain, weight loss, pruritus
- Complete medication review: prescribed drugs, over-the-counter medications, herbal supplements, illicit drugs, injection drug use
- Alcohol intake: current and past consumption in units per week, consider AUDIT-C scoring
- Metabolic syndrome features: central obesity, hypertension, diabetes/insulin resistance, dyslipidemia
- Travel history, occupational exposures, tick bites
- Family history of liver disease
- For children: add maternal, neonatal, nutritional, and developmental history
Physical Examination Priorities
Focus on 1:
- Body mass index calculation
- Abdominal examination for hepatosplenomegaly, ascites, and signs of chronic liver disease
- Signs of portal hypertension or hepatic decompensation
Core Laboratory Workup
Standard Liver Aetiology Screen (Core Panel)
Order these tests immediately for all adults with abnormal liver enzymes 1:
- Abdominal ultrasound
- Hepatitis B surface antigen (HBsAg)
- Hepatitis C antibody (with reflex PCR if positive)
- Anti-mitochondrial antibody (AMA)
- Anti-smooth muscle antibody
- Antinuclear antibody (ANA)
- Serum immunoglobulins (particularly IgG)
- Simultaneous serum ferritin and transferrin saturation
Additional Tests for Specific Patterns
For marked ALT elevations (>1000 U/L), also test for 1:
- Hepatitis A and E
- Cytomegalovirus
For cholestatic patterns with personal/family history of autoimmune disease or inflammatory bowel disease, consider primary sclerosing cholangitis and obtain MRI, as no diagnostic serologic markers exist. 1
To confirm hepatobiliary origin of isolated alkaline phosphatase elevation, order 2:
- Gamma-glutamyl transferase (GGT) or
- Alkaline phosphatase isoenzymes
Pediatric Modifications
For children, the core panel should 1:
- Include: anti-liver kidney microsomal antibody, coeliac antibodies, alpha-1-antitrypsin level, and caeruloplasmin (age >3 years)
- May omit: ferritin and transferrin saturation
- Urgent action: Discuss any abnormalities with an inherited metabolic disease specialist
- Neonatal cholestasis (conjugated bilirubin >25 μmol/L) requires urgent pediatric consultation
Pattern Recognition and Next Steps
Hepatocellular Pattern (Elevated ALT/AST)
ALT is the most sensitive and specific marker for hepatocellular injury. 3, 4
If NAFLD risk factors present (metabolic syndrome, BMI >25, type 2 diabetes) 1:
- Calculate FIB-4 or NAFLD Fibrosis Score
- FIB-4 <1.3 or NFS ≤1.455 indicates low risk of advanced fibrosis
- For patients >65 years, use higher cut-offs: FIB-4 <2.0 or NFS <0.12
- Consider second-line tests: Enhanced Liver Fibrosis (ELF) score or elastography (FibroScan/ARFI)
Cholestatic Pattern (Elevated ALP/GGT)
Always confirm hepatic origin before proceeding with hepatobiliary workup. 2 ALP can be elevated from bone disease, pregnancy, or other non-hepatic sources.
Immediate Referral Criteria
Refer urgently to hospital if 1:
- Unexplained clinical jaundice
- Suspicion of hepatic or biliary malignancy
- Dilated bile ducts on imaging
- Synthetic dysfunction: elevated INR, low albumin, elevated bilirubin
- ALT ≥3× ULN with total bilirubin ≥2× ULN (Hy's Law criteria) 2
Specialist Referral Indications
Refer to hepatology/gastroenterology for 1:
- Hepatitis B (HBsAg positive)
- Hepatitis C (antibody and PCR positive)
- Autoimmune hepatitis (raised IgG ± positive autoantibodies)
- Primary biliary cholangitis (cholestatic enzymes + positive AMA)
- Primary sclerosing cholangitis (cholestatic enzymes ± inflammatory bowel disease history)
- Hemochromatosis (ferritin elevated AND transferrin saturation >45%)
- Advanced liver disease (cirrhosis features, portal hypertension, FibroScan >16 kPa)
- Negative extended workup with persistent abnormalities and no NAFLD risk factors
Common Pitfalls to Avoid
Do not assume isolated elevated ferritin indicates hemochromatosis. 1 Isolated ferritin elevation commonly occurs in dysmetabolic iron overload syndrome associated with alcohol excess, NAFLD, and other chronic liver diseases. Hemochromatosis requires BOTH elevated ferritin AND transferrin saturation >45%.
Do not assume elevated ALP is hepatic without confirmation. 2 Always verify with GGT or ALP isoenzymes before pursuing hepatobiliary workup.
Maintain low threshold for pediatric referral. 1 Common adult causes are less frequent in children, and the differential diagnosis is broader.
For alcohol-related liver disease with AUDIT score >19, refer to alcohol dependency services. 1
Extended Panel (Reserve for Unclear Cases)
Only order extended testing when the core panel fails to identify a cause. 1 The extended panel is not routinely indicated as <5% of patients with abnormal liver tests have specific liver disease requiring immediate treatment, and only 1.3% require urgent intervention. 1