X-linked hypophosphatemia (XLH) is a genetic, progressive and lifelong disorder characterised by low levels of phosphate in the blood (hypophosphataemia) due to excess of a regulating factor known as fibroblast growth factor 23. Phosphate plays an essential role in human cellular processes as well as in tissue structure and function. Clinical manifestations of XLH usually begin in childhood causing weakened skeletal bones, lower limb deformities, height loss and dental abscesses. Fixed skeletal deformities plus chronic hypophosphataemia, leads to the development of debilitating physical issues for the patient, including fractures, osteoarthritis, hearing problems and serious dental problems. This continues into adolescence and adulthood. Adults experience levels of pain, stiffness and fatigue that significantly impact on their mobility, and performance of daily activities, limiting social, family and work life and their mental health. A recent paper reported an “unexpected increase in mortality in later life” in a population with XLH). The current study plans to provide more information on this finding based on a larger group of patients and utilising more information on healthcare and deaths. Primary care records of a cohort of people who may have XLH will be analysed and the outputs reviewed by clinical experts and those classified as possible, likely or very likely XLH will be included in the study. Life expectancy will be estimated for this group and for a comparison group matched by year of birth, IMD sex and ethnicity. Cause of death and associated risk factors will be investigated and reported.
This study will further investigate a recent finding that life expectancy in XLH is shorter than that in the general population. CPRD records will be analysed for a cohort of patients with diagnoses or clinical features which are suggestive of XLH, these records will be categorised as possibly, likely or highly likely to have the condition based on inclusion and exclusion criteria, the outputs will be validated by clinical expert review of CPRD diagnosis, symptoms, laboratory findings and prescribing, and HES clinical data. Life expectancy will be estimated using life tables for the XLH cohort and a year of birth, sex, IMD and ethnicity matched comparator. Kaplan-Meier plots of time to death will be provided and Cox proportional hazard models will investigate factors associated with early death. Cause of death will be described in both strata and cause specific death will be investigated if there is a cluster of underlying cause of death within one disease category in the XLH cohort.
The results could provide greater understanding of the long-term consequences of XLH which would allow improved focus of healthcare in this XLH population.
Death; cause of death; year of birth; sex; ethnicity; X-linked hypophosphatemia (XLH); diagnoses that could mimic XLH, such as cystinosis or fibrous dysplasia to be defined in the study); socio-economic status; smoking status; Laboratory values,(phosphate; alkaline phosphatase, calcium, parathyroid; glomerular filtration rate; alanine transferase; bicarbonate); primary care prescriptions (activated vitamin D preparation; oral phosphate preparations; bicarbonate; potassium or calcium supplements).
Craig Currie - Chief Investigator - Pharmatelligence Limited t/a Human Data Sciences
Nick Denholm - Corresponding Applicant - Harvey Walsh Ltd
David Heaton - Collaborator - Harvey Walsh Ltd
Gillian Logan - Collaborator - Kyowa Kirin Ltd.
Kassim Javaid - Collaborator - University of Oxford
Kevin Lock - Collaborator - Kyowa Kirin Ltd.
Linda McNamara - Collaborator - Kyowa Kirin Ltd.
Xiaocong Marston - Collaborator - Harvey Walsh Ltd
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation