From the Guidelines
Elevated alkaline phosphatase (ALP) levels can be caused by several conditions affecting the liver, bones, and other organs, with the most common liver-related causes including biliary obstruction, hepatitis, cirrhosis, and infiltrative liver diseases, as well as bone-related causes such as Paget's disease, osteomalacia, and bone metastases 1. The causes of elevated ALP levels can be broadly categorized into liver-related and non-liver related causes. Liver-related causes include:
- Biliary obstruction (such as gallstones or tumors blocking bile ducts)
- Hepatitis
- Cirrhosis
- Infiltrative liver diseases Non-liver related causes include:
- Paget's disease
- Osteomalacia
- Bone metastases
- Fracture healing
- High bone turnover states Other significant causes of elevated ALP levels include pregnancy (particularly the third trimester), certain medications (like phenytoin and certain antibiotics), hyperthyroidism, sepsis, and some cancers (especially those with bone metastases) 1. It is essential to determine which isoenzyme is increased to identify the source tissue, as this guides further diagnostic workup and treatment. Measurements of GGT can indicate whether pathologically elevated ALP is of hepatic or nonhepatic origin, and concomitantly elevated GGT can help confirm that an elevated ALP originates from the liver and indicates cholestasis 1. Key points to consider when evaluating elevated ALP levels include:
- The severity of abnormal aminotransferase can be classified as mild, moderate, or severe
- Cholestasis can be due to obstruction of biliary outflow or impairment in bilirubin uptake
- If abnormal ALP levels are seen without impairment of other liver enzymes, the etiology is suspected to be cholestatic in origin
- If ALP is elevated in isolation, a suspicion of cholestatic disease is raised 1.
From the Research
Causes of Elevated Alkaline Phosphatase
Elevated alkaline phosphatase (ALP) levels can be caused by a variety of factors, including:
- Bone involvement from malignancy or Paget's disease 2
- Sepsis, which can be caused by gram-negative organisms, gram-positive organisms, or fungal sepsis 2
- Biliary obstruction, which can be caused by malignant obstruction or common bile duct stones 2
- Acquired immunodeficiency syndrome (AIDS) 2
- Mycobacterium avium intracellulare (MAI) infection 2
- Cytomegalovirus infection 2
- Dilantin toxicity 2
- Diffuse liver metastases 2
- Benign intrahepatic disease, including liver hemangiomas, sarcoid hepatitis, lead toxicity, and drug-induced cholestasis 2
- Underlying malignancy, including infiltrative intrahepatic malignancy, bony metastasis, and both hepatic and bone metastasis 3
- Bone disease, including Paget's disease and osteoporosis 3, 4
- Unsuspected parenchymal liver disease 3
- Non-malignant infiltrative liver disease 3
- Other disorders, including benign familial hyperphosphatasemia 5
- Fractures, which can cause a rise in serum ALP levels 6
Specific Conditions Associated with Elevated ALP
Certain conditions are more commonly associated with elevated ALP levels, including:
- Metastatic intrahepatic malignancy 3
- Paget's disease 2, 4
- Osteoporosis 4
- Primary hyperparathyroidism 4
- Chronic renal failure on hemodialysis 4
- Osteomalacia 6
- Liver disease, including liver damage and cirrhosis 2, 4
Diagnostic Considerations
When evaluating elevated ALP levels, it is essential to consider the clinical context and potential causes. Measurement of serum ALP levels within the first week after a fracture may be necessary to avoid the distorting influences of the fracture itself 6. Additionally, the use of a new immunoradiometric assay (IRMA) for bone alkaline phosphatase (B-ALP) may be helpful in diagnosing and monitoring patients with metabolic bone disease 4.