Raised alkaline phosphatase

Possible causes of increased levels of plasma alkaline phosphatase include: (1,2)

• hepatobiliary disease including:
  • cholestasis: increased synthesis of hepatocyte ALP and increased secretion of high molecular weight form into plasma; elevations of ALP of up to 10 times normal levels
  • hepatocyte disease, such as viral hepatitis which cause moderate elevations in ALP
• bone disease - bone isoenzyme of alkaline phosphatase, reflecting increased osteoblastic activity, may be raised in:
  • Paget's disease
  • osteomalacia and rickets
  • vitamin D deficiency
    • profiles of serum calcium, phosphate and alkaline phosphatase may sometimes be helpful in the diagnosis of vitamin D deficiency
      • note though that serum calcium and phosphate concentrations only fall in longstanding, symptomatic, vitamin D deficiency; there is an increase in levels of alkaline phosphatase (total and bone-specific) increase early in vitamin D deficiency
        • this is a non-specific finding, but may be helpful in diagnosing individuals with otherwise unexplained elevations in alkaline phosphatase
  • renal osteodystrophy
  • bone metastases
  • primary bone tumour e.g. sarcoma
  • recent fracture
  • hyperparathyroidism may also lead to elevated alkaline phosphatase levels because the overproduction of parathyroid hormone (PTH) causes increased bone turnover, which includes both the breakdown and formation of bone
  • growing child - especially at puberty
• during pregnancy the placenta secretes its own isoenzyme which raises total alkaline phosphatase concentration
• malignancies resulting in expression of ALP-like gene e.g. seminomas

In determining whether a raised ALP is of hepatic or bony origin e.g. in metastasis of breast cancer, the following may be useful:

• other test of hepatic function e.g. GGT
• electrophoresis separation of isoenzymes
• bone scan
• ultrasound scan of liver

Sometimes it is useful to look at the relationship of ALP to bilirubin and lactate dehydrogenase (LD) levels

Notes:

• If alkaline phosphatase is raised in an asymptomatic patient and serum bilirubin, liver transaminases, creatinine, adjusted calcium, thyroid function, and blood count are normal:
  • consider growth spurts in adolescents, pregnancy in women, drugs, and age related increases
  • as most likely sources are either bone or liver, differentiate by measuring GGT (raised in liver) and investigate accordingly
  • for liver cases investigate with abdominal ultrasound scan (cholestasis and hepatic space occupying lesion) and antimitochondrial antibodies (primary biliary cirrhosis)
  • for bone cases investigate vitamin D

Reference:

1. Sharma U, Pal D, Prasad R. Alkaline phosphatase: an overview. Indian J Clin Biochem. 2014 Jul;29(3):269-78.
2. Šmíd V. Liver tests. Cas Lek Cesk. 2022 Spring;161(2):52-56.