From the Guidelines
Investigations for high alkaline phosphatase (ALP) should begin with a thorough clinical assessment and targeted laboratory tests, prioritizing fractionated ALP to determine the source of elevation, followed by liver function tests, and imaging studies as necessary. The most recent and highest quality study, 1, published in 2024, recommends a step-wise approach to evaluating elevated ALP, including the use of gamma-glutamyl transferase (GGT) testing, 5′nucleotidase levels, and DBIL to inform the etiology of ALP elevations.
Key initial steps include:
- Ordering fractionated ALP to determine if the elevation is from liver, bone, intestine, or placenta
- Conducting liver function tests (AST, ALT, GGT, bilirubin)
- Complete blood count, calcium, phosphate, and vitamin D levels
- If liver origin is suspected, obtaining hepatitis serology, abdominal ultrasound, and considering autoimmune markers like ANA and AMA
- For bone-origin ALP, ordering PTH levels, bone-specific ALP, and bone imaging studies
According to 1 and 1, if GGT is normal with elevated ALP, consideration should be given to bone disease, medication effects, or pregnancy. In children, transient hyperphosphatasemia may occur without pathology, as noted in 1. Persistent unexplained elevations warrant referral to a specialist (hepatologist or endocrinologist), as emphasized in 1. The investigation pathway is determined by the patient's clinical presentation, as ALP elevations reflect increased osteoblastic activity in bone disorders or biliary obstruction/hepatocellular injury in liver conditions. Medications like certain antibiotics and anticonvulsants can also cause elevations and should be reviewed during assessment, as highlighted in 1.
In terms of imaging, 1 suggests that patients with elevated ALP suspected to be liver in origin and no alternative etiology should undergo transabdominal US to assess for dilated intra- or extrahepatic ducts and gallstones as the possible cause. Further evaluation with dynamic contrast-enhanced CT, MRI, or CEUS may be required if biliary obstruction is identified.
Ultimately, the approach to investigating high ALP should be guided by the most recent and highest quality evidence, with a focus on determining the underlying cause and prioritizing the patient's clinical presentation and potential morbidity, mortality, and quality of life outcomes.
From the Research
Investigations for High Alkaline Phosphatase (ALP)
- High ALP levels can be an indicator of bone or liver disease, and investigations are necessary to determine the underlying cause.
- Bone-specific alkaline phosphatase (B-ALP) is an isoform of ALP found in bone tissue and can be used as a marker of bone turnover 2, 3.
- Total alkaline phosphatase (TAP) levels can be elevated in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), but B-ALP levels are not always correlated with disease activity 2.
- In patients with spinal cord injury, ALP and B-ALP levels can be affected by various factors, including exercise and treatment with certain medications 3.
- B-ALP has been shown to be a useful biomarker in the diagnosis of osseous metastases in patients with malignant carcinomas, with a pooled sensitivity and specificity of 0.74 and 0.80, respectively 4.
- In patients with chronic kidney disease, bone alkaline phosphatase (BALP) has been identified as a promising predictor of mortality and a useful biomarker of bone turnover 5.
Diagnostic Tests
- Serum TAP and B-ALP levels can be measured using various assays, including colorimetric assays, lectin precipitation, enzyme immunoassay, and immunoradiometric assay 6.
- The choice of assay can affect the results, and B-ALP measurements may be more specific than TAP measurements in certain clinical situations 6.
- Receiver-operating characteristic (ROC) curve analysis can be used to evaluate the diagnostic validity of different assays and biomarkers 6, 4.
Clinical Applications
- B-ALP and BALP can be used as biomarkers in the diagnosis and management of various bone and mineral disorders, including osteoporosis, Paget's disease, and chronic kidney disease-mineral and bone disorder (CKD-MBD) 3, 5.
- These biomarkers can provide valuable information on bone turnover and can be used to monitor the effectiveness of treatment 5.