From the Guidelines
Elevated alkaline phosphatase (ALP) levels are most commonly caused by liver diseases such as cholestatic liver disease, cirrhosis, and chronic hepatitis, as well as bone diseases like Paget’s disease and bony metastases, as indicated by the most recent study 1. The causes of increased ALP can be broadly categorized into hepatic and non-hepatic origins. Hepatic causes include:
- Cholestatic liver disease, such as primary biliary cholangitis and primary sclerosing cholangitis
- Intrahepatic or extrahepatic bile duct obstruction
- Drug-induced cholestasis
- Cirrhosis and chronic hepatitis Non-hepatic causes include:
- Bone disease, such as Paget’s disease, bony metastases, or fracture
- Pregnancy, due to placental production
- Certain cancers and inflammatory bowel disease To determine the source of elevated ALP, measurements of gamma-glutamyl transpeptidase (GGT) can be helpful, as GGT is found in the liver but not in bone 1. Concomitantly elevated GGT can confirm that an elevated ALP originates from the liver and indicates cholestasis, as stated in the study 1. Isolated elevated ALP of hepatic origin that persists over time suggests a chronic cholestatic process, such as partial bile duct obstruction or primary biliary cholangitis 1. In clinical practice, it is essential to consider the patient's clinical history, medications, and other relevant factors to determine the underlying cause of elevated ALP levels, as emphasized by the study 1.
From the Research
Causes of Increased Alkaline Phosphatase (ALP)
- Paget's disease of bone (PDB) is a common cause of elevated serum ALP levels, as it is characterized by disorganized bone remodeling with enhanced bone resorption and formation 2.
- In PDB, the accelerated bone resorption and formation are not closely coupled, leading to the production of large quantities of new bone matrix and an increase in ALP levels 2.
- Bisphosphonate treatment for PDB can also lead to increased ALP levels, as it can cause mineralization defects and hypocalcemia with secondary hyperparathyroidism 3.
- Other conditions, such as bone pain, bowing of long bones, enlarged skull, and hearing loss, can also be associated with elevated ALP levels in PDB 2.
- It is essential to note that ALP levels can be influenced by various factors, and a comprehensive diagnosis should consider the entire clinical picture, including laboratory values and radiographic findings 4, 2.
Diagnostic Considerations
- Serum total ALP is recommended as a first-line biochemical screening test in combination with liver function tests for screening the presence of metabolically active PDB 4.
- Radionuclide bone scans and targeted radiographs are also recommended for fully and accurately defining the extent of metabolically active disease in patients with PDB 4.
- Nuclear scintigraphy of the bone is considered the most sensitive test for confirming the diagnosis of PDB 2.
Treatment Implications
- Bisphosphonates, such as zoledronic acid, pamidronate, alendronate, and risedronate, are the mainstay of treatment for PDB 2.
- Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB 4.
- Patients who do not tolerate bisphosphonates can be treated with calcitonin 2.