Suggested protocol for investigation and referral of an isolated asymptomatic raised alkaline phosphatase in an adult in primary care

A reasonable approach in adults with an isolated raised serum alkaline phosphatase is careful medical and drug history and physical examination (1–4)

• if patients are asymptomatic but have raised alkaline phosphatase levels of unknown cause, then the test for alkaline phosphatase should be repeated with GGT to confirm if liver origin
• two main sources of alkaline phosphatase are liver and bone, although there are also intestinal and placental isoforms. Elevations may be physiological or pathological. Common causes for raised alkaline phosphatase (5):
  • physiological
    • third trimester of pregnancy
    • adolescents, due to bone growth
    • benign, familial
  • pathological
    • bile duct obstruction
    • primary biliary cirrhosis
    • primary sclerosing cholangitis
    • drug induced cholestasis, e.g. anabolic steroids
    • metastatic liver disease
    • bone disease e.g., Pagets
    • heart failure

Recommended investigation for isolated raised alkaline phosphatase in primary care (1):

• if not already done then check liver and bone profiles to exclude other raised indices
  • baseline investigations for a raised alkaline phosphatase include:
    • bone profile
      • may include bone isoenzyme of alkaline phosphatase - not widely available
    • LFTs
    • GGT - a marker of cholestasis and biliary disease
    • 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 (2)
    • FBC, ESR, CRP - raised inflammatory markers would be suggestive of causes such as undiagnosed malignancy or metastatic disease

Raised hepatic alkaline phosphatase level: raised serum alkaline phosphatase with raised GGT

• raised GGT indicate a hepatic rather than bony origin for raised ALP levels
  • note that in some patients a raised level may originate from both liver and bone (for example, in metastatic cancer), but they are likely to have symptoms or a history of cancer (3)
    
    
• if the serum ALP level is raised but less than 1.5 times the upper reference limit then the test should be repeated in 1-3 months (1,3)
  
  
• if the level is more than 1.5 times the upper reference limit or persistently raised
  • then
    • liver ultrasound examination to detect cholestasis or an infiltrative liver lesion - if abnormal then hepatology referral
    • measurement of antimitochondrial antibodies to detect primary biliary cirrhosis - if positive then hepatology referral
      
      
  • if these tests produce normal results and the serum alkaline phosphatase level is less than 1.5 times the upper reference limit
    • patient should be evaluated clinically for symptoms in six months
      
      
  • if alkaline phosphatase persistently more than 1.5 times the upper reference limit and ultrasound examination and serology give normal results
    • hepatologist referral for consideration of a liver biopsy and further specialist imaging

Raised non-hepatic alkaline phosphatase level: raised serum alkaline phosphatase but normal GGT

• normal serum GGT indicates that the raised serum alkaline phosphatase level is non-hepatic
  • probable causes include vitamin D deficiency, Paget's disease of bone (increased incidence from age 55 years onwards, especially in those over 75 years of age), or growth spurts in adolescents
  • less common causes include:
    • bone tumours and healing fractures
    • hypercalcaemia of primary hyperparathyroidism may be masked by vitamin D deficiency - becomes apparent after vitamin D replacement (3)

If vitamin D levels are in the normal range and the serum alkaline phosphatase level is less than 1.5 times the upper reference limit, then observation of the patient should be continued, with further investigations if patients develop symptoms (3)

• uncertainty whether the absence of symptoms in the presence of non-hepatic serum alkaline phosphatase levels more than 1.5 times the upper reference limit should be investigated further (3)
  • however bone scintigraphy may be considered in patients who are vitamin D replete to identify asymptomatic Paget's disease, as this may be an indication for active treatment (3)

In summary (1):

• if the alkaline phosphatase is < 1.5 upper limit of normal (ULN) then
  • recheck in 1-3 months
    
    
• if alkaline phosphatase persistently > 1.5 ULN *
  • then this an indication for further investigation and referral (if unexplained by investigations above)
    
    
• if alkaline phosphatase >3 ULN (single measurement) then referral and further investigation indicated
  
  
• referral to secondary care is indicated if alkaline phosphatase is raised > 2 ULN (if unexplained by laboratory tests) **
  
  
• values up to 20% over ULN are likely to be statistical rather than clinical 'abnormals'
  

* Different guidance states different time periods for when an asymptomatic raised alkaline phosphatase above 1.5 x the upper limit of normal is persistent as either not giving a time period at all (4), 3 months (5) or 6 months (1) - in my own clinical practice I would be prudent and if an asymptomatic raised alkaline phosphatase has persisted for 2 months AND investigations have not identified a cause then I would seek expert advice. Obviously if a patient has become symptomatic or has other abnormal liver function tests then this would prompt seeking expert advice per se. Also if an indentiable cause of the raised alkaline phosphatase has been identified this is managed appropriately depending on cause (6)

** This indicates that if an asymptomatic alkaline phosphatase is persistently above 2 x the upper limit of normal AND all the suggested blood tests (including antimitochondrial antibodies) are negative then expert advice should be sought

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 (2):
  • 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. Clinical Knowledge Summaries (accessed 6/4/07). How should I investigate an isolated 'slightly raised' alkaline phosphatase in an asymptomatic adult? www.cks.library.nhs.uk
2. Huang MJ, Liaw YF.Clinical associations between thyroid and liver diseases.J Gastroenterol Hepatol. 1995 May-Jun;10(3):344-50.
3. NHS Exeter Clinical Laboratory - Alkaline Phosphatase (Accessed 1/9/19)
4. Shipman KE et al. Interpreting an isolated raised serum alkaline phosphatase level in an asymptomatic patient.BMJ. 2013 Apr 3;346:976
5. City and Hackney CCG. Abnormal Liver Function Tests (LFTs) in Adults (Accessed 1/9/19)
6. Personal Opinion - Dr Jim McMorran, Editor in Chief GPnotebook (September 2/1/19)