Undetectable ALT
Alanine aminotransferase (ALT) is an enzyme involved in the transfer of an amino group from the amino acid, alanine, to alpha-ketoglutaric acid to produce glutamate and pyruvate. ALT is located primarily in liver and kidney, with lesser amounts in heart and skeletal muscle. ALT activity in the liver is 3000-fold higher than in plasma. Increased ALT activity is more specific for liver damage than increased aspartate aminotransferase (AST) activity.
ALT requires vitamin B6 (pyridoxal-5'-phosphate, P5P) as a catalytic cofactor. In an attempt to standardize aminotransferase assays, the International Federation of Clinical Chemistry (IFCC) recommends that laboratories add excess P5P to their enzyme reagents so that these assays accurately measure enzyme activity independently of vitamin B6 status. Unfortunately, less than 50% of ALT assays incorporate exogenous 5P5.
Our clinical laboratory performs ALT on Beckman AU5800 instruments. Beckman ALT reagent is not supplemented with P5P. Approximately 0.3% of our ALT results are reported as <3 IU/L. A chart review of 160 patients with ALT results <3 IU/L was undertaken to determine if the undetectable ALT results were associated with known clinical causes of P5P deficiency.
The most common associations in our patient population were:
- Carbidopa/levodopa therapy
- Gastric sleeve surgery
- Small bowel resections
- Malnutrition
- Hydralazine therapy
- End stage renal disease and dialysis
- End stage liver disease
People with poor renal function, including those with end-stage renal disease and chronic renal insufficiency, often have low vitamin B6 concentrations. Plasma PLP concentrations are also low in patients receiving maintenance kidney dialysis or intermittent peritoneal dialysis, as well as those who have undergone a kidney transplant, perhaps due to increased metabolic clearance of P5P.
P5P is absorbed in the jejunum. Patients with celiac disease, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, and other malabsorptive autoimmune disorders tend to have low plasma P5P concentrations.
Plasma P5P concentrations tend to be very low in people with liver disease due to alcohol dependence. Alcohol produces acetaldehyde, which decreases net P5P formation by cells and competes with P5P in protein binding. As a result, P5P in cells might be more susceptible to hydrolysis by membrane-bound phosphatase.
Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels. Medicines that reduce levels of vitamin B6 include:
- Cycloserine (Seromycin)
- Hydralazine (Apresoline)
- Isoniazid, used to treat tuberculosis
- Penicillamine
- Theophylline (TheoDur)
- Pyrazinamide
- Levodopa/carbidopa
- Anti-epileptics - valproic, carbamazepine, phenytoin
Carbidopa and hydralazine were most commonly associated with undetectable ALT in our institution, most likely due to our very active neurology and nephrology services.
This small study supports the recommendation of the IFCC that excess 5P5 should be added to all ALT reagents. Without this modification, many individuals with early liver disease may go undetected.
