What are the causes of low Liver Function Tests (LFTs)?

Causes of Low Liver Function Tests (LFTs)

Low liver function tests typically indicate reduced liver synthetic function or decreased enzyme activity, which can occur in various clinical settings from advanced liver disease to non-hepatic conditions.

Primary Causes of Low LFTs

Advanced Liver Disease

• Cirrhosis/End-stage liver disease: In advanced liver disease, enzyme levels may paradoxically normalize or decrease as functioning hepatocytes diminish 1, 2
• Advanced fibrosis: As fibrosis progresses, there may be fewer functioning hepatocytes to release enzymes, resulting in "normal" or low enzyme values despite significant disease 2
• Chronic hepatitis: Long-standing viral hepatitis can lead to decreased enzyme production as the disease progresses 1

Decreased Synthetic Function

• Low albumin: Indicates impaired protein synthesis by the liver, a key marker of liver function rather than injury 2
• Abnormal A/G ratio: A low albumin-to-globulin ratio can represent early liver dysfunction even before enzyme elevation occurs 2
• Coagulopathy: Decreased production of clotting factors (reflected by elevated INR/PT) indicates impaired synthetic function 1

Medication-Related Causes

• Statin therapy: Can cause transient elevations but may lead to decreased enzyme levels with hepatocyte damage 3
• Hepatotoxic drugs: Prolonged exposure to hepatotoxic medications can deplete functioning hepatocytes, resulting in lower enzyme levels 1, 4

Non-Hepatic Causes

• Malnutrition/Protein deficiency: Leads to decreased protein synthesis including albumin and enzymes 2
• Hemodilution: Fluid overload states can dilute serum concentrations of liver enzymes 5
• Chronic renal failure: Can affect liver enzyme levels and metabolism 1

Clinical Approach to Low LFTs

Initial Assessment

1. Determine which LFTs are low:

   • Synthetic function tests: Albumin, prothrombin time/INR
   • Enzyme tests: ALT, AST, ALP, GGT

2. Evaluate for context:

   • Low enzymes with normal synthetic function may be less concerning
   • Low enzymes with impaired synthetic function (low albumin, elevated INR) suggests advanced liver disease 1, 2

3. Consider AST/ALT ratio:

   • Ratio >1 suggests advanced fibrosis/cirrhosis
   • Ratio >2 strongly suggests alcoholic liver disease 2

Further Investigation

1. Non-invasive fibrosis assessment:

   • FIB-4 score or liver elastography to evaluate for advanced fibrosis 2
   • Abdominal ultrasound to assess liver structure 2

2. Additional testing based on clinical suspicion:

   • Viral hepatitis serologies
   • Autoimmune markers (ANA, ASMA, AMA)
   • Metabolic liver disease workup (alpha-1-antitrypsin, ceruloplasmin, iron studies) 2

3. Consider liver biopsy if diagnosis remains unclear despite non-invasive testing 1

Special Considerations

Immune Checkpoint Inhibitor Therapy

• Patients on immunotherapy may develop immune-related hepatitis with variable LFT patterns 1
• Monitor closely for signs of liver dysfunction despite normal or low enzymes

COVID-19 and Liver Function

• COVID-19 can affect liver function with variable patterns of LFT abnormalities 1
• Approximately 15% of hospitalized COVID-19 patients have abnormal LFTs 1

Medication Management

• For patients with low LFTs, carefully review all medications for potential hepatotoxicity 4
• Consider dose adjustments for medications with hepatic metabolism in patients with evidence of liver dysfunction 4

When to Refer to Hepatology

Referral to hepatology is recommended in these scenarios 2:

• Persistent low albumin or abnormal A/G ratio despite addressing non-hepatic causes
• Evidence of advanced fibrosis on non-invasive testing
• Presence of concerning features (splenomegaly, thrombocytopenia)
• Development of jaundice or signs of hepatic decompensation

Key Pitfalls to Avoid

1. Don't assume normal enzymes mean normal liver function: Liver enzymes reflect injury, not function; synthetic parameters (albumin, INR) better reflect liver function 2

2. Don't overlook non-hepatic causes: Low albumin can result from malnutrition, protein-losing enteropathy, or nephrotic syndrome 2

3. Don't miss advanced liver disease: Paradoxically, very advanced liver disease may present with normal or low enzymes as functioning hepatocytes diminish 1, 2

4. Don't delay evaluation: Low synthetic function tests (albumin, elevated INR) warrant prompt evaluation even with normal enzymes 2