What is the Differential Diagnosis of Hyperphosphatasemia?

Patient Presentation
An 8-year-old male came to clinic for a second opinion of an elevated serum alkaline phosphatase level. He originally went to an emergency room for abdominal pain (diagnosed with constipation) and had laboratory testing that showed an isolated alkaline phosphatase of 2442 U/L (nl 70-325 U/L). An initial workup completed by his private physician included a liver and gallbladder ultrasound, esophagogastroduodenoscopy and colonoscopy which were negative. Four weeks later he had another alkaline phosphatase that was 2378 U/L and was referred for a second opinion. He has a history of constipation that improves with fiber and Miralax®. He has been growing well and has had no fevers, chills, sweats, nausea, emesis, diarrhea, rashes, cough, pain or difficulty sleeping. The family history is positive for diabetes, stroke and constipation. There is no other history of gastrointestinal disease including liver or gallbladder nor bone disease. The review of systems was extensively reviewed and was negative.

The pertinent physical exam showed a healthy appearing male with a growth parameters that were 25-50% except for weight which was 10% and was consistent with previous measurements. The abdominal and skeletal examinations were negative. The laboratory evaluation currently 5 weeks after the second testing included tests for rickets, endocrinopathies, kidney disease and malignancies and was negative. The alkaline phosphatase was 184 U/L at this time, and isoenzymes were not performed. The diagnosis of probable benign transient hyperphosphatasemia of childhood was made although this child was older than 5 years, and for this reason another level was suggested to be checked again in 4 weeks with the primary care physician. As this is a benign disease no other specific treatment was recommended.

Alkaline Phosphatase (AlkPhos) is found mainly in the bone and liver but also in the intestine, kidney, placenta, lung, neutrophils, lymphocytes, and endothelium. The levels are significantly increased over normal adult levels during childhood and adolescence. They increase during puberty, during pregnancy and increase again slightly in older people. They can also be increased after liver and biliary surgeries. There are some differences between boys and girls with boys having a slightly higher AlkPhos than girls.

Benign hyperphosphastemia of infancy and childhood is a benign disease with an unknown etiology. It is often found incidentally during routine blood analysis. It is most common in children but has been reported in adults. Diagnostic criteria include:

  • < 5 years of age in the absence of symptoms or presence of an unrelated illness such as seizures
  • No evidence of bone or liver disease clinically or biochemically
  • Isoenzyme analysis with an elevation in both bone and liver fraction
  • AlkPhos increased 3-50 times normal range for age
  • AlkPhos returns to normal level within 4 months

Learning Point
The differential diagnosis of an elevated AlkPhos includes:

  • Normal/Factitious – patient is a child but is compared to adult norms
  • Bone
    • Healing fracture
    • Osteomalacia
    • Rickets
  • Liver
    • Cholestasis
    • Intrinsic liver disease
    • Malignancy with liver metastases
  • Malignancies
    • Gynecologic
    • Primary liver
    • Primary bone
    • Metastasis, particularly to liver
  • Other
    • Benign transient hyperphosphatasemia
    • Bowel perforation
    • Congestive heart failure
    • Infectious – cytomegalovirus, Epstein-Barr virus
    • Infarction (especially in healing phase) – bowel, kidney, lung, myocardium, pancreas, spleen
    • Malabsorption
    • Pancreatitis
    • Pregnancy
    • Renal disease
    • Sarcoidosis
    • Secondary hyperparathyroidism
    • Sepsis
    • Surgery – liver, biliary
    • Ulcerative colitis

Questions for Further Discussion
1. What would be indications for a gastrointestinal consultation?
2. What other symptoms might suggest a skeletal abnormality?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Bile Duct Diseases and Bone Diseases.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Bakerman S, Bakerman P, Strausbauch P. Bakerman’s ABC’s of Interpretive Laboratory Data. 4th edit. Interpretive Laboratory Data Inc. Scottsdale, AZ. 2000:33-35.

Tolaymat N, de Melo MC. Benign transient hyperphosphatasemia of infancy and childhood. South Med J. 2000 Dec;93(12):1162-4.

Yang L, Grey V. Pediatric reference intervals for bone markers. Clin Biochem. 2006 Jun;39(6):561-8.

George J, Denney-Wilson E, Okely AD, Hardy LL, Aitken R. The population distributions, upper normal limits and correlations between liver tests among Australian adolescents. J Paediatr Child Health. 2008 Oct;44(10):579-85.

Fialkowski EA, Winslow ER, Scott MG, Hawkins WG, Linehan DC, Strasberg SM.Establishing “normal” values for liver function tests after reconstruction of biliary injuries. J Am Coll Surg. 2008 Nov;207(5):705-9.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

  • Systems Based Practice
    23. Differing types of medical practice and delivery systems including methods of controlling health care costs and allocating resources are known.
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.


    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital