Differential Diagnosis of Elevated PLP with Low Alkaline Phosphatase
While hypophosphatasia is the primary genetic cause of combined high PLP and low alkaline phosphatase, Wilson disease presenting as acute liver failure is the most important alternative diagnosis to exclude, as it requires urgent specific treatment and presents with markedly subnormal alkaline phosphatase (typically <40 IU/L) alongside elevated PLP. 1
Primary Consideration: Wilson Disease
In acute liver failure presentations, Wilson disease characteristically shows markedly low serum alkaline phosphatase (typically <40 IU/L) with a ratio of alkaline phosphatase to total bilirubin of <2, occurring alongside Coombs-negative hemolytic anemia, coagulopathy, and relatively modest aminotransferase elevations (typically <2000 IU/L). 1 This represents a medical emergency requiring immediate evaluation and treatment.
Medication-Induced Low Alkaline Phosphatase
- Antiresorptive medications, particularly bisphosphonates, can lower alkaline phosphatase levels and should be reviewed in the medication history. 1
- When alkaline phosphatase is suppressed by medications, PLP levels may appear relatively elevated due to reduced enzymatic degradation, though this mechanism differs from the genetic deficiency seen in hypophosphatasia. 2, 3
Inflammatory States and Low Albumin Conditions
- In conditions associated with low albumin (such as inflammation), plasma alkaline phosphatase activity influences PLP concentration measurements, and red cell PLP measurements are more reliable than plasma measurements for differentiating true from apparent vitamin B6 status. 2, 1
- However, inflammation typically causes a fall in plasma PLP rather than elevation, so this would not explain the combination of high PLP and low alkaline phosphatase. 2
Critical Diagnostic Distinction
The relationship between alkaline phosphatase and PLP is quantitatively inverse and logarithmic: a significant negative linear relationship exists where log PLP = 5.99-2.76 log ALP (r = -0.85, P < 0.001). 4 This mathematical relationship helps distinguish pathological states:
- In hypophosphatasia, tissue nonspecific alkaline phosphatase functions as an ectoenzyme to regulate extracellular PLP levels, and its deficiency leads to markedly increased circulating PLP (mean 1174 nM, range 214-3839 nM versus normal 57 ± 26 nM). 3
- In Wilson disease, the low alkaline phosphatase reflects acute hepatocyte destruction rather than genetic enzyme deficiency, but the clinical context (hemolysis, coagulopathy, specific biochemical ratios) distinguishes it. 1
Practical Clinical Approach
When encountering combined high PLP and low alkaline phosphatase:
Immediately assess for acute liver failure signs (coagulopathy, encephalopathy, hemolysis) to exclude Wilson disease, which requires urgent ceruloplasmin, 24-hour urinary copper, and slit-lamp examination. 1
Review medication history for bisphosphonates or other antiresorptive agents that could suppress alkaline phosphatase. 1
Consider vitamin B6 challenge testing (20 mg pyridoxine hydrochloride daily for 2 days) if hypophosphatasia is suspected, as this achieves sensitivity of 100% and specificity of 96% for identifying ALPL mutation carriers when post-challenge PLP exceeds 500 nmol/L. 5
Measure additional substrates including phosphoethanolamine and inorganic pyrophosphate, which are characteristically elevated in hypophosphatasia but not in other causes of low alkaline phosphatase. 6
Important Caveat
Performing assays of circulating PLP concentration alone to assess vitamin B6 nutrition may be misleading in disorders associated with altered alkaline phosphatase activity, as the enzyme directly regulates extracellular PLP levels. 3 Therefore, PLP levels should always be interpreted in conjunction with prevailing serum alkaline phosphatase levels, as the metabolism of these compounds is closely inter-related. 4