title: The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool.
abstract: Background Alkaptonuria is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National Alkaptonuria Centre in Liverpool has been using 2 mg nitisinone (NTBC) off-license for all patients in the United Kingdom with alkaptonuria and monitoring the tyrosine metabolite profiles. Methods Patients with confirmed alkaptonuria are commenced on 2 mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing NTBC. Thereafter, monitoring and clinical assessments are performed annually. Results Urine homogentisic acid concentration decreased from a mean baseline 20,557 µmol/24 h (95th percentile confidence interval 18,446-22,669 µmol/24 h) by on average 95.4% by six months, 94.8% at one year and 94.1% at two year monitoring. A concurrent reduction in serum homogentisic acid concentration of 83.2% compared to baseline was also measured. Serum tyrosine increased from normal adult reference interval to a mean ± SD of 594 ± 184 µmol /L at year-two monitoring with an increased urinary excretion from 103 ± 81 µmol /24 h at baseline to 1071 ± 726 µmol /24 h two years from therapy. Conclusions The data presented represent the first longitudinal survey of NTBC use in an NHS service setting and demonstrate the sustained effect of NTBC on the tyrosine metabolite profile.
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.|2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Milan
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.|2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hughes
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.|2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Davison
authors.affiliation: 2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Devine
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Usher
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Curtis
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.
authors.forename: Milad
authors.initials: M
authors.lastname: Khedr
authors.affiliation: 2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
authors.affiliation: 1 Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool, UK.|2 Bone and Joint Research Group, Musculoskeletal Biology, University of Liverpool, Liverpool, UK.
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath
mesh_terms: D000328:Adult; D000368:Aged; D000474:Alkaptonuria / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000652:urine; D002853:Chromatography, Liquid; D003512:Cyclohexanones / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D050560:Homogentisate 1,2-Dioxygenase / Q000172:deficiency; D006713:Homogentisic Acid / Q000097:blood / Q000652:urine; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D009579:Nitrobenzoates / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry; D014443:Tyrosine / Q000097:blood / Q000652:urine; D006113:United Kingdom
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D050560:Homogentisate 1,2-Dioxygenase; C077073:nitisinone; D006713:Homogentisic Acid
keywords: Alkaptonuria; inborn errors of metabolism; nitisinone; tyrosine