Investigation of asymptomatic raised alkaline phosphatase

Baseline investigations for a raised alkaline phosphatase include (1,2):

• bone profile
  • may include bone isoenzyme of alkaline phosphatase - not widely available
• LFTs
• GGT - a marker of cholestasis and biliary disease
  • GGT is abundant in the liver and also present in the kidney, intestine, prostate and pancreas but not in bone - thus can be useful in confirming that an elevated alkaline phosphatase is of liver and not bony origin
• vitamin D - vitamin D deficiency can be the cause an asymptomatic raised alkaline phosphatase
• U+Es - renal osteodystrophy can cause a raised alkaline phosphatase
• TFTs - may be associated with elevation of alanine aminotransferase and alkaline phosphatase, which is mainly of bone origin, in hyperthyroidism (3)
• FBC, ESR, CRP - raised inflammatory markers would be suggestive of causes such as undiagnosed malignancy or metastatic disease
  

If a raised alkaline phosphatase level is determined to be of liver origin then first line investigations in a patient include (1):

• liver ultrasonography, any dilatation should be investigate by ERCP
• serum antimitochondrial antibodies - to identify possible PBC

If serologic test for antimitochondrial levels is negative and ultrasound is normal but the alkaline phosphatase remains increased more than 50% above the normal level then other investigations such as liver biopsy and either magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography are suggested (1). However if the increase in alkaline phosphatase is less than 50% and the patient has no symptoms and the results of all liver-enzymes are normal, then observation alone has been suggested as the appropriate management (1).

Notes:

• determination whether the elevated alkaline phosphatase is of liver or bone origin:
  • electrophoresis to determine origin of alkaline phosphatase - not widely available
  • measurement of GGT (gamma glutamyltransferase) or 5'- nucleotidase - levels of these enzymes are generally raised in parallel with the elevation in alkaline phosphatase in patients with liver disorders, but they are not increased in patients with bone disorders
• Sometimes it is useful to look at the relationship of ALP to bilirubin and lactate dehydrogenase (LD) levels (4)

• If alkaline phosphatase is raised in an asymptomatic patient and serum bilirubin, liver transaminases, creatinine, adjusted calcium, thyroid function, and blood count are normal (5):
  • 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:

• NEJM 2000; 342 (17): 1266-1271.
• Clinical Knowledge Summaries (accessed 6/4/2007). How should I investigate an isolated 'slightly raised' alkaline phosphatase in an asymptomatic adult? www.cks.library.nhs.uk
• Huang MJ, Liaw YF.Clinical associations between thyroid and liver diseases.J Gastroenterol Hepatol. 1995 May-Jun;10(3):344-50.
• NHS Exeter Clinical Laboratory - Alkaline Phosphatase (Accessed 1/9/19)
• Shipman KE et al. Interpreting an isolated raised serum alkaline phosphatase level in an asymptomatic patient.BMJ. 2013 Apr 3;346:976