What causes low Alanine Transaminase (ALT) levels?

Causes of Low Alanine Transaminase (ALT) Levels

Low ALT levels are primarily caused by vitamin B6 deficiency, advanced liver disease with reduced hepatocyte mass, and are associated with frailty and increased mortality risk. 1, 2, 3

Primary Causes of Low ALT

Low ALT levels (typically <17 IU/L) can be attributed to several factors:

1. Vitamin B6 (Pyridoxine) Deficiency

   • ALT requires pyridoxal 5-phosphate (PLP, the active form of vitamin B6) as a cofactor
   • Studies show a direct linear correlation between low ALT activity and low vitamin B6 levels 2
   • Supplementation with vitamin B6 can normalize ALT levels in deficient patients 3

2. Advanced Liver Disease

   • Extensive liver damage leads to reduced enzyme production due to fewer functioning hepatocytes 1
   • Paradoxically low ALT despite advanced disease can occur in alcohol-related liver disease 1

3. Medications and Substances

   • Anabolic steroids (reduce liver enzyme production by up to 40%) 1
   • Nicotinic acid/Niacin (consistently reduces liver enzymes) 1
   • Sex hormones (estrogens, progesterone, testosterone) 1

4. Medical Conditions

   • Hyperthyroidism 1
   • End-stage renal disease and hemodialysis 3
   • Reduced glomerular filtration (GFR < 70 mL/min) 1
   • Severe burns and sepsis 1
   • Frailty syndrome 2, 4

Clinical Significance of Low ALT

Low ALT levels have important prognostic implications:

• Marker of Frailty: Low ALT serves as a biomarker for increased incidence of frailty 2, 4

• Mortality Predictor: Multiple studies have demonstrated that low ALT levels are independently associated with increased long-term all-cause mortality:

  • In middle-aged adults (HR=1.6; 95% CI 1.34-1.92) 4
  • In patients with coronary heart disease (HR 1.11; 95% CI: 1.03-1.19) 5

• Common in Hospitalized Patients: Over one-third of patients hospitalized in internal medicine departments have low ALT levels 2

Diagnostic Considerations

When evaluating low ALT levels:

• Vitamin B6 Assessment: Consider measuring plasma pyridoxal 5-phosphate (PLP) levels, especially in patients with end-stage renal disease or on hemodialysis 3

  • Normal values of plasma PLP are 5-50 μg/L (20-200 nmol/L) 6

• Comprehensive Liver Panel: Include AST, alkaline phosphatase, GGT, total and direct bilirubin 1

• Synthetic Function Assessment: Check prothrombin time/INR and albumin 1

• Consider Populations at Risk: Elderly, alcoholics, renal dialysis patients, post-operative patients, those with infections or critical illness 6

Management Implications

For patients with low ALT levels:

• Vitamin B6 Supplementation: Consider in deficient patients, especially those on hemodialysis 3

  • Oral pyridoxine HCl (30 mg daily) has been shown to normalize ALT levels in deficient patients 3

• Monitoring for Frailty: Low ALT may indicate need for frailty assessment and preventive interventions 2, 4

• Cardiovascular Risk Assessment: Given the association with mortality in coronary heart disease patients 5

Common Pitfalls

• Overlooking Low ALT: While elevated ALT often triggers clinical concern, low ALT is frequently overlooked despite its prognostic significance 2, 4

• Normal Range Interpretation: The upper limit of normal for ALT varies, but studies suggest optimal cut-offs of 29 IU/L for men and 22 IU/L for women 7. Values below these thresholds, particularly <17 IU/L, may warrant attention 4

• Confounding by Inflammation: Inflammation can affect plasma PLP levels but minimally affects red blood cell concentrations 6

• Transaminasemia as Marker: The correlation between ALT levels and liver inflammation is imperfect, with 30% of patients with normal ALT showing significant inflammation 6