Abstract: Increased serum levels of alkaline phosphatase (ALP) are widely recognized as a biochemical marker of many disorders afecting the liver or bone. However, the approach for patients with low ALP phosphatase is not well-established. Low serum ALP is an epiphenomenon of many severe acute injuries and diseases. Persistently low serum ALP may be secondary to drug therapy (including antiresorptives) or a variety of acquired disorders, such as malnutrition, vitamin and mineral defciencies, endocrine disorders, etc. Hypophosphatasia, due to pathogenic variants of the ALPL gene, which encodes tissue non-specifc ALP, is the most common genetic cause of low serum ALP. Marked bone hypomineralization is frequent in severe pediatric onset cases. However, adult forms of hypophosphatasia usually present with milder manifestations, such as skeletal pain, chondrocalcinosis, calcifc periarthritis, dental problems, and stress fractures. The diagnostic approach to these patients is discussed. Measuring several ALP substrates, such as pyrophosphate, pyridoxal phosphate, or phosphoethanolamine, may help to establish enzyme defciency. Gene analysis showing a pathogenic variant in ALPL may confrm the diagnosis. However, a substantial proportion of patients show normal results after sequencing ALPL exons. It is still unknown if those patients carry unidentifed mutations in regulatory regions of ALPL, epigenetic changes, or abnormalities in other genes

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