Khedr, Milad 
ORCID: 0000-0002-4998-2397
(2023)
Pathophysiological and therapeutic studies in Alkaptonuria.
Doctor of Medicine thesis, University of Liverpool.
|
Text
201173311_Oct2023.pdf - Author Accepted Manuscript Download (6MB) | Preview |
Abstract
Alkaptonuria (AKU) is a rare inborn error of tyrosine metabolism (OMIM 203500) caused by a deficiency in the homogentisate dioxygenase enzyme (HGD, EC 1.13.11.5) which leads to increased homogentisic acid in body fluids and tissues. This results in the formation of a melanin-like pigment in a process called ochronosis. Ochronosis is the main pathophysiological process in AKU. It changes the mechanical properties of tissues and gives rise to the various manifestations of AKU. These include features such as stones (kidney, prostate, salivary and gall bladder), ruptures (tendons, muscle, ligaments), hearing impairment, external ocular and auricular ochronosis, cardiac (mainly aortic) valve disease, bone fractures and most significantly, arthritis. The management of AKU has been mainly supportive without addressing the underlying pathophysiological mechanisms. However, nitisinone (NTBC), a competitive reversible inhibitor of the hydroxyphenylpyruvic acid dioxygenase enzyme (HPPD, EC 1.13.11.27), can decrease urinary excretion of homogentisic acid by 98.8%. NTBC is already licensed and has been used for over two decades for the treatment of hereditary tyrosinaemia type 1 (HT-1) in children. Since 2012, NTBC has been used off-label in the NHS England designated National Alkaptonuria Centre (NAC), at the Royal Liverpool University Hospital. Data from the NAC cohort suggest that NTBC reverses ochronosis. In October 2020 and following the positive clinical outcomes of SONIA 2, NTBC has been licensed for the treatment of AKU in adults. Since the biochemical deficit is present since birth, treatment with NTBC to modify the course of AKU seems logical. However, NTBC causes a significant rise in serum tyrosine which has been associated with cognitive impairment in children, skin rash, vitiligo, cataract, and potentially sight-threatening keratopathy. These serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. It is hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. An analytical method has been developed to measure tyrosine and phenylalanine tracers. Pulse injection with L-[13C9]tyrosine and L-[d8]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC in AKU patients and also measure concentrations of tracers in AKU mice, healthy volunteers and AKU patients. NTBC significantly increased the tyrosine pool size in humans. It also increased the tyrosine concentrations in murine tissues, suggesting that NTBC increases tyrosine not just in serum but also in tissues (i.e., acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC-related acquired tyrosinosis that should be overcome to ensure the safe use of NTBC in AKU.
| Item Type: | Thesis (Doctor of Medicine) |
|---|---|
| Divisions: | Faculty of Health and Life Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 30 Nov 2023 10:23 |
| Last Modified: | 30 Nov 2023 10:23 |
| DOI: | 10.17638/03173844 |
| Supervisors: |
|
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173844 |
Dimensions
Dimensions
