What is the approach to managing a patient with deranged liver function tests (LFTs)?

Approach to Deranged Liver Function Tests

Immediate Action: Do Not Simply Repeat Tests

Do not adopt a "wait and see" approach by simply repeating abnormal liver tests—instead, immediately investigate the underlying cause unless you have high clinical certainty the abnormality is transient (e.g., recent viral illness, muscle injury, or short-term medication exposure). 1, 2

• 84% of abnormal liver tests remain abnormal at 1 month, and 75% remain abnormal at 2 years, making routine repeat testing an inefficient strategy that delays diagnosis of treatable conditions 1, 2
• Repeating tests wastes resources and delays diagnosis of hepatitis C, NAFLD, and alcohol-related liver disease, which frequently present with mild elevations but progress to cirrhosis 2

Red Flags Requiring Urgent Referral

Immediately refer to secondary care if any of the following are present: 1, 3

• Unexplained clinical jaundice 1, 3
• Suspected hepatobiliary malignancy 1, 3
• Evidence of synthetic liver failure (prolonged INR, hypoalbuminemia) 3
• Marked derangement with clinical instability 3

Initial Clinical Assessment

History—Specific Details to Obtain

Obtain the following targeted information: 1, 3

• Alcohol consumption: Quantify in units per week (harmful drinking: ≥50 units/week in men, ≥35 units/week in women) 3
• Complete medication review: All prescribed medications, over-the-counter drugs, herbal supplements, injecting drug use 1, 3
• Viral hepatitis risk factors: Country of birth/ethnicity (for hepatitis B/C prevalence), injection drug use, incarceration history 1, 3
• Metabolic risk factors: BMI, central obesity, hypertension, diabetes/insulin resistance, dyslipidemia 1, 3
• Specific symptoms: Jaundice, abdominal pain, weight loss, pruritus 1
• Travel history, occupational exposure, tick bites, muscle injury 1
• Family history of liver disease or autoimmune conditions 1
• For children: Maternal, neonatal, nutritional, and developmental history 1

Physical Examination

Perform targeted examination including: 1

• Body mass index calculation 1
• Abdominal examination for hepatosplenomegaly, ascites, and signs of chronic liver disease 1

Core Laboratory Investigation Panel

Order the following tests simultaneously (do not stage them): 1, 2, 3

• Complete blood count with differential 2, 3
• Comprehensive metabolic panel 2, 3
• Hepatitis B surface antigen 1, 2, 3
• Hepatitis C antibody (with reflex PCR if positive) 1, 2, 3
• Anti-mitochondrial antibody 1, 2, 3
• Anti-smooth muscle antibody 1, 2, 3
• Antinuclear antibody 1, 2, 3
• Serum immunoglobulins 1, 2, 3
• Simultaneous serum ferritin and transferrin saturation 1, 2, 3
• Abdominal ultrasound 1, 2, 3

Additional Testing for Specific Scenarios

If ALT >1000 U/L, add: 1, 2, 3

• Hepatitis A serology 1, 2, 3
• Hepatitis E serology 1, 2, 3
• Cytomegalovirus testing 1

For children, modify the panel to include: 1

• Anti-liver kidney microsomal antibody 1
• Coeliac antibodies 1
• Alpha-1-antitrypsin level 1
• Caeruloplasmin (age >3 years) 1

If cholestatic pattern with personal/family history of autoimmune disease or inflammatory bowel disease: 1

• Consider primary sclerosing cholangitis; MRI may be required at outset as no diagnostic serological markers exist 1

Risk Stratification for Fibrosis

For suspected NAFLD (metabolic risk factors present): 2, 3

• Calculate FIB-4 or NAFLD Fibrosis Score as first-line fibrosis risk stratification 2, 3
• Consider referral for further fibrosis evaluation if scores suggest advanced disease 3

For alcohol-related liver disease: 3

• Refer to alcohol services for dependency treatment 3
• Perform risk stratification with Fibroscan/ARFI elastography 3

Monitoring Patients on Hepatotoxic Medications

If patient is receiving potentially hepatotoxic medications (lopinavir-ritonavir, chloroquine, hydroxychloroquine, tocilizumab): 1, 2

• Monitor liver tests twice weekly 1, 2
• Monitor more frequently if abnormal liver function develops 1, 2
• Withhold off-label COVID-19 treatment if moderate-to-severe (category 2-3) liver injury occurs 1

Specific Disease Management Considerations

Hepatitis B

If hepatitis B surface antigen positive and systemic corticosteroids or immunosuppressants planned for ≥7 days: 1, 3

• Initiate antiviral therapy to prevent HBV reactivation and hepatitis flare 1, 3
• Do not stop oral nucleoside antiviral therapy for HBV to avoid risk of reactivation 1
• Concomitant use of tenofovir with lopinavir-ritonavir is relatively contraindicated; consider temporary switch to entecavir 1

Hepatitis C

If hepatitis C antibody positive: 1

• Confirm with PCR testing 1
• Concomitant use of protease inhibitor-containing DAA regimens with lopinavir-ritonavir is contraindicated 1
• Continue DAAs if already initiated 1

Drug-Induced Liver Injury

If suspected: 3

• Review timing of medication use relative to liver abnormality development 3
• Exercise clinical judgment regarding major contributor 3
• Consider discontinuation of potentially hepatotoxic medications 3
• Note: Statins rarely cause liver injury and are safe in patients with pre-existing abnormal liver enzymes 3

Referral Criteria to Gastroenterology/Hepatology

Refer patients with: 1, 3

• Positive hepatitis B or C serology 1, 3
• Autoimmune hepatitis (raised IgG ± positive autoantibodies) 1
• Primary biliary cholangitis (cholestatic enzymes + positive anti-mitochondrial antibody) 1, 3
• Primary sclerosing cholangitis (cholestatic enzymes ± inflammatory bowel disease history) 1, 3
• Haemochromatosis (raised ferritin and transferrin saturation >45%) 1
• Abnormal liver tests with negative extended workup and no NAFLD risk factors 3
• Evidence of advanced liver disease or cirrhosis 3
• Dilated bile ducts on imaging (requires urgent assessment) 1

Critical Pitfalls to Avoid

Do not make these common errors: 2

• Do not assume mild elevations are insignificant—NAFLD, hepatitis C, and alcohol-related liver disease often present with mild abnormalities but progress to cirrhosis 2
• Do not wait for normalization in children—the differential diagnosis is broader and requires low threshold for pediatric referral 1, 2
• Do not stop investigating if tests normalize—normal liver tests do not exclude chronic liver disease like hepatitis C or NAFLD 2
• Do not attribute abnormalities to medications without proper investigation—84% of "transient" abnormalities persist 2
• Do not confuse isolated elevated ferritin with haemochromatosis—this is commonly seen in dysmetabolic iron overload syndrome (alcohol excess, NAFLD) and does not reflect haemochromatosis unless transferrin saturation is also >45% 1