What is the management approach for a patient with normal liver enzymes but risk factors or symptoms suggestive of liver disease?

Management of Patients with Normal Liver Enzymes but Risk Factors or Symptoms Suggestive of Liver Disease

Despite normal liver enzymes, patients with risk factors or symptoms suggestive of liver disease require systematic evaluation because liver blood tests correlate poorly with the severity of underlying liver pathology, and significant liver disease—including cirrhosis—can exist with normal transaminases. 1

When to Check Liver Blood Tests Despite Normal Baseline Values

Non-Specific Symptoms Warranting Evaluation

• Fatigue, nausea, or anorexia should prompt liver blood testing even if prior tests were normal, as 75% of patients with autoimmune hepatitis present with these non-specific symptoms, and these treatable diseases are often diagnosed late 1
• The majority of people with late-stage liver disease remain undiagnosed because liver disease develops silently without signs or symptoms 1

High-Risk Conditions Requiring Periodic Monitoring

Inflammatory bowel disease (ulcerative colitis or Crohn's disease):

• Monitor liver blood tests periodically with a low threshold for investigation, as nearly 10% develop primary sclerosing cholangitis 1
• Primary sclerosing cholangitis-inflammatory bowel disease increases both liver disease complications and colorectal cancer risk 1

Pre-existing autoimmune diseases:

• Check liver blood tests when clinical symptoms change to suggest liver involvement, such as new-onset pruritus suggesting primary biliary cholangitis 1

Metabolic dysfunction-associated steatotic liver disease (MASLD) risk factors:

• Apply case-finding strategies using non-invasive tests in individuals with cardiometabolic risk factors, radiological signs of hepatic steatosis, type 2 diabetes, or obesity with additional metabolic risk factors—even with normal liver enzymes 1
• Use a stepwise approach starting with FIB-4 score, followed sequentially by transient elastography to rule out advanced fibrosis, which predicts liver-related outcomes 1

Hepatotoxic drug use:

• Drugs commonly implicated include carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine, and methotrexate 1
• Methotrexate requires special monitoring with non-invasive markers of fibrosis to prevent dose-dependent liver fibrosis 1

Role of Liver Biopsy in Patients with Normal Transaminases

Liver biopsy should be considered in HCV-positive patients with normal liver function tests who are HCV RNA-positive and being considered for treatment 1

Evidence Supporting Biopsy Despite Normal Enzymes

• In one study, 11% of patients with chronic active hepatitis or active cirrhosis had normal ALT levels 1
• Another study found more than 50% of patients with chronic active hepatitis, chronic persistent hepatitis, or cirrhosis had normal ALT levels 1
• Clinical parameters alone correctly predict cirrhosis in less than one-third of cases 1

Liver biopsy is valuable for assessing inflammation status, potential fibrosis progression, and presence or absence of cirrhosis in viraemic patients, whether or not liver function tests are abnormal 1

Specific Clinical Scenarios

NAFLD with Normal Liver Enzymes

• Methotrexate can be used in DMARD-naive patients with NAFLD who have normal liver enzymes and liver function tests and no evidence of advanced liver fibrosis 1
• Noninvasive testing to diagnose and stage liver fibrosis should be considered prior to initiating methotrexate 1
• More frequent monitoring (every 4-8 weeks) is required in this population 1

Hepatitis B Core Antibody Positive Patients

• Frequent monitoring of viral load and liver enzymes alone is recommended over prophylactic antiviral therapy for patients initiating bDMARDs (other than rituximab) or tsDMARDs who are hepatitis B core antibody positive and surface antigen negative 1
• These patients should be comanaged with a hepatologist 1

Anti-HCV Positive, PCR Negative Patients

• Screen for other liver diseases including autoimmune hepatitis and hemochromatosis 1
• Follow up annually until natural history is better known 1
• Liver biopsy may be recommended if viraemia returns or liver enzymes flare 1

Common Pitfalls to Avoid

• Do not assume normal liver enzymes exclude significant liver disease, particularly in chronic hepatitis C, autoimmune liver disease, and early cirrhosis 1
• Statins are not contraindicated in NAFLD and may provide cardiovascular benefit—very rare to cause drug-induced liver injury 1
• More than 30% of elevated transaminases spontaneously normalize during follow-up, but persistently normal values in high-risk patients still warrant investigation 2