Bone and liver alkaline phosphatase isoform profile in children with benign transient hyperphosphatasemia at early age

Benign transient hyperphosphatasemia (BTH) is characterized by markedly elevated serum alkaline phosphatase (ALP) in young children without clinical signs of hepatobiliary or metabolic bone disease. BTH is typically discovered incidentally, and its etiology and ALP isoform profile is largely unexplored.

We identified 63 children with BTH at 1 or 2 years of age within the VIDI study, a randomized-controlled vitamin D supplementation trial, initially comprising 987 infants followed longitudinally to 6-8 years of age. Assessments included total ALP, bone ALP (BALP) and liver ALP isoforms by gel electrophoresis with lectin precipitation, BALP Ostase^® immunoassays (Liaison^® and IDS-iSYS analyzers), and BALP isoforms (B/I, B1 and B2) by HPLC.

In children with BTH, total ALP levels reached up to 11-fold above the upper reference interval limit, while BALP was increased 2- to 17-fold. Gel electrophoresis showed increased bone, liver 1 and liver 2 ALP levels, with pronounced anodal migration of liver ALP in BTH. In contrast, children with non-typical BTH, defined by the absence of pronounced anodal migration of liver ALP, had relatively higher bone ALP than liver ALP levels. HPLC profiling revealed that the BALP B2 isoform was increased in BTH.

BTH was associated with concurrent elevation of bone and liver ALP isoforms and characteristic anodal migration, likely reflecting enhanced sialylation resulting in prolonged serum half-life. Increased expression of the BALP B2 isoform and specific liver ALP isoforms suggests differential glycosylation. Site-specific glycoproteomic analyses are warranted to define ALP glycoform signatures underlying BTH.