Interpreting an isolated raised serum alkaline phosphatase level in an asymptomatic patientBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f976 (Published 03 April 2013) Cite this as: BMJ 2013;346:f976
- Kate Elizabeth Shipman, specialist trainee year 4, metabolic medicine,
- Ashley David Holt, foundation year 2 doctor,
- Rousseau Gama, consultant chemical pathologist
- Correspondence to: K E Shipman firstname.lastname@example.org
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 γ-glutamyltransferase (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
A 51 year old asymptomatic woman presented to her general practitioner for cascade screening for familial hypercholesterolaemia. Blood tests revealed a normal full blood count, renal function, thyroid function, lipid profile, glucose levels, bone profile, and liver profile except for an isolated increased alkaline phosphatase (ALP) concentration at 171 U/L (reference interval 30-130).
What is the next investigation?
ALP is found in high concentrations in liver, bone, kidney, intestine, and placenta. In adults, circulating ALP is predominantly of hepatic and bony origin. Serum ALP levels increase in pregnancy and by the third trimester can be twofold to fourfold higher as a result of a physiological increase in placental ALP. Reference intervals are age and sex related, gradually increasing from age 40 to 65 years, especially in women, and can be up to threefold to sevenfold higher in rapidly growing adolescents.1 Reference intervals contain 95% of the population, therefore 2.5% of the normal population have values above the upper reference limit. The combined analytical and biological variation for serum ALP is around 8%,1 2 and levels increase by up to 6% if analysis is delayed for 96 hours in samples stored at room temperature.3 For example, an ALP result of 125 U/L could be between 108 U/L and 143 U/L, spanning the upper reference limit. Minor increases in serum ALP levels are therefore more likely to be analytical, physiological, or statistical anomalies rather than indicating disease.
An evidence base is lacking on the differential diagnosis and outcome of an isolated increased serum ALP level—that is, a raised serum ALP level in the presence of normal serum levels of bilirubin, transaminases (alanine aminotransferase or aspartate aminotransferase, or both), and calcium. It is reassuring that over 95% of ambulatory patients with an unexplained raised serum ALP level during a multiphasic screening examination developed no overt disease during a two year follow-up.4 Furthermore, all important disease in the remaining 5% would have been detected by simple history, examination, and routine laboratory investigations.4
In a case series of patients admitted to hospital, an isolated raised serum ALP level was associated with a variety of medical illnesses, including congestive cardiac failure (16%), benign bone disease (8%; fractures and osteomyelitis), hyperthyroidism (2%), and end stage renal disease (5%).5 In over 50% of patients, serum ALP levels returned to the normal range within one year and mostly within three months. Usually there was a known clinically obvious cause, such as metastatic malignancy, for a persistently isolated raised serum ALP level, which was more likely if the initial level was more than 1.5 times the upper reference limit.5
The next step
A reasonable approach in adults with an isolated raised serum ALP level is therefore a careful medical and drug history (table⇓) and physical examination.4 6 7 Key features include abdominal pain or swelling, unintentional weight loss, back pain, bone pain, clinical indicators of liver disease, congestive cardiac failure, and end stage chronic kidney disease.4 5 If patients are asymptomatic but have raised ALP levels of unknown cause, then the test for ALP should be repeated with γ-glutamyltransferase to confirm and define the abnormality and adjusted calcium levels, thyroid function tests, renal profile, and haemoglobin levels4 checked within four weeks if not part of the original profile. These tests should identify the major pathological causes, with anaemia indicating potential systemic illness. Haematological, renal, thyroid, and calcium abnormalities should be further investigated and managed appropriately; however, if the results are normal then the raised ALP level is isolated (further investigations are discussed below).
Raised hepatic ALP level: raised serum ALP with raised serum γ-glutamyltransferase level
Raised γ-glutamyltransferase levels indicate a hepatic rather than bony origin for raised ALP levels.6 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.
If the serum ALP level is raised but less than 1.5 times the upper reference limit then the test should be repeated in three months. If the level is more than 1.5 times the upper reference limit or persistently raised, then appropriate investigations would be a liver ultrasound examination to detect cholestasis or an infiltrative liver lesion8 and measurement of antimitochondrial antibodies to detect primary biliary cirrhosis, and any abnormalities should be investigated accordingly.8 9 Although primary biliary cirrhosis is uncommon, if diagnosed early treatment improves outcome. If these tests produce normal results and the serum ALP level is less than 1.5 times the upper reference limit, then patients should be evaluated clinically for symptoms in six months as further investigation is not cost effective.4 10 If, however, the serum ALP level is persistently more than 1.5 times the upper reference limit and ultrasound examination and serology give normal results, the patient should be referred to a hepatologist for consideration of a liver biopsy and further specialist imaging.8 9
Raised non-hepatic ALP level: raised serum ALP but normal serum γ-glutamyltransferase level
A normal serum γ-glutamyltransferase level indicates that the raised serum ALP level is non-hepatic and most likely bony in origin and due to vitamin D deficiency,11 Paget’s disease of bone (increasing in incidence from age 55 years onwards and becoming particularly significant in those over 75 years of age),12 13 or growth spurts in adolescents. Other uncommon causes of increased serum bony ALP levels, such as bone tumours and healing fractures, will be clinically evident. The hypercalcaemia of primary hyperparathyroidism may be masked by vitamin D deficiency and only become apparent after vitamin D replacement.14
In patients with raised or persistently isolated increases in non-hepatic serum ALP levels and no symptoms, serum vitamin D levels should be measured and any hypovitaminosis D managed. If vitamin D levels are in the normal range and the serum ALP 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.4 It is questionable whether the absence of symptoms in the presence of non-hepatic serum ALP levels more than 1.5 times the upper reference limit should be investigated further,15 but bone scintigraphy may be considered in patients who are vitamin D replete to identify asymptomatic Paget’s disease, as some12 but not all13 suggest that this is an indication for active treatment.
Studies to clarify the ALP isoform may be considered in the presence of diagnostic uncertainty and noticeable increases in serum ALP levels. Outside pregnancy, increased levels of serum placental ALP may be due to tumour secretion but rarely increases the total serum level. Increased serum intestinal ALP levels may occur with intestinal disease or as a familial benign entity. Increased serum renal ALP levels may be encountered in renal diseases. Rarely, ALP binds to an immunoglobulin to form macroALP, which may be detected by precipitation studies. MacroALP is of no significance but has been associated with inflammatory bowel disease.16
As the patient was asymptomatic, took no drugs, and had no abnormal physical findings, her general practitioner repeated the test for serum ALP level. Her serum γ-glutamyltransferase level was also checked. This was normal, as was her serum ALP, now at 121 U/L. The patient was reassured and needed no further follow-up.
Cite this as: BMJ 2013;346:f976
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor, head of department of academic endocrinology, diabetes, and metabolism, Hull York Medical School; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at email@example.com.
Contributors: All authors performed the literature search. KES wrote the first draft of the manuscript, with RG and ADH involved in revisions. All authors approved the final article. RG is the guarantor.
Competing interests: All authors have completed the ICMJE form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; externally peer reviewed.
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