Assessment of disease progression in the rare disease alkaptonuria by quantitative image analysis

• Main Author: Taylor, Leah Frances
• Other Authors: Gallagher, James
• Published: University of Liverpool 2018
• Subjects: 617.4
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.755716

Alkaptonuria (AKU) arises from a genetic deficiency of homogentisate 1,2 dioxygenase (HGD) an enzyme involved in tyrosine metabolism. AKU is characterised by high circulating homogentisic acid (HGA) some of which is deposited as ochronotic pigment in connective tissues, mainly cartilage, leading to multisystemic damage dominated by premature severe osteoarthropathy. Pathological changes in the spine as a result of ochronosis can be imaged using fluorine-18 labelled sodium fluoride positron emission tomography (18F-NaF PET). This imaging modality allows quantitative assessment of focal bone remodelling by measuring the uptake of 18F into the hydroxyapatite crystal of bone and calcified cartilage. The mean standardised uptake value (SUVm), a mathematically derived ratio of tissue radioactivity in a region of interest (ROI) and the decay corrected injected dose per kilogram of the patient's body weight has common place in oncology. The functional changes that 18F-NaF PET detects have led to this modality being re-evaluated for its advantages in skeletal diseases such as osteoarthritis and AKU. AKU patients underwent a variety of clinical testing and imaging including 18F-NaF PET scanning at the Royal Liverpool University Hospital. Semi-quantitative analysis of the PET scans was utilised to investigate the anatomical distribution of increased 18F uptake. Quantitative SUVms were also obtained as a measure of Fluoride uptake in the bony vertebrae and cartilaginous intervertebral discs (IVD). Other clinical data were taken from the case notes for correlation. The anatomical distribution of increased 18F uptake was confirmed to primarily affect the weight bearing joints. The quantitative SUVm methodology revealed a striking variation between AKU and control SUVms in the IVDs thought to represent calcification of the IVDs in AKU. The mechanism proposed is that calcium hydroxyapatite or calcium pyrophosphate dihydrate are deposited in the fibrocartilaginous IVDs in AKU due to biochemical alterations of the disease. 18F binds to the calcium deposits resulting in high SUVms compared to the control. The SUVms obtained from the vertebrae in both AKU and control patients are similar across the lumbar and thoracic spine suggesting that generalised rates of bone turnover in AKU and control patients are comparable. With age the AKU SUVms of the IVDs followed an interesting trend (the inverted 'U' shaped trend) that was strikingly different to that of the control group that appears to remain stable with age. It is proposed that the AKU trend demonstrates the process of disc degeneration. In the bony vertebrae, an age-related decline in SUVm was observed in both AKU and control groups, thought to represent reduced bone turnover with age. Correlations were made with the IVD SUVms and other clinical data. Reduced vertebrae SUVm and increased IVD SUVm were found to be associated with higher clinical scores, pain scores, excessive spinal curvature angles, lower BMD T-scores and spinal flexibility measurements. The proposed reason for this is primarily due to reduced BMD with age and spinal arthropathy associated with calcified IVDs. All in all, this thesis has provided new insights into spinal arthropathy in AKU. The utilisation of novel quantitative techniques demonstrated in this thesis can be used to aid in clinical interpretation of PET scans as well as providing a measure of disease severity and to analyse disease progression and response to therapy.