Clinical presentation of adults with persistently low alkaline phosphatase activity: a retrospective multicentre, cross-sectional study in Germany.

Objective: Persistently low serum alkaline phosphatase (ALP) activity is the hallmark of hypophosphatasia (HPP). However, low ALP values are not commonly recognised in routine clinical practice, often leading to delayed HPP diagnosis. Determining symptoms associated with persistently low ALP activity may facilitate a timelier diagnosis and improved treatment of patients with HPP. This study aimed to evaluate the signs and symptoms associated with low ALP.

Design: Retrospective, multicentre, cross-sectional study.

Setting: Medical records of adults with low ALP activity collected in 18 German clinics and large medical centres with medical specialty in endocrinology, diabetology, rheumatology and osteology were assessed. Serum ALP activity, medical history, previous diagnoses, laboratory values and symptoms were analysed.

Participants: Records were screened to identify patients≥18 years with ALP activity below the lower limit of the normal range within the last 5 years. Exclusion criteria were oncological or haematological disorders, intensive care at the time of low ALP measurement and having more than one ALP measurement in the normal range or above. Data from 849 patients with ≥1 low ALP value (median age: 44.0, min 18.0, max 90.0), including a subset of 32 patients with documented HPP diagnosis, were analysed.

Results: The study cohort presented with a spectrum of clinical manifestations and diagnostic profiles. Patients with HPP displayed typical symptoms, in particular musculoskeletal pain and fractures, more often than patients without HPP diagnosis (n=817). Among patients without HPP, 26.6% were diagnosed with hypothyroidism. 35 patients displayed 4+ clinical and biochemical signs typical for HPP that were attributed to differential diagnoses, such as rheumatic diseases, fibromyalgia and osteoporosis/osteopenia, suggesting the possibility of underlying HPP in some cases.

Conclusion: Most patients in this study had hypophosphatasemia without further evaluation, highlighting the need for greater awareness of low ALP levels in clinical practice. Recognising low ALP levels, especially when accompanied by symptoms like pain, musculoskeletal and dental abnormalities, is crucial for timely diagnosis and improved patient care.