Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

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Abstract

Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701–900 (105), 901–1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR ( p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR ( p < 0.001), while HPLA/TYR ratio decreased ( p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.

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Most cited references 32

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Natural history of alkaptonuria.

Lynn Gerber, Marjan Huizing, A L Fitzpatrick … (2002)

Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria. We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms. The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation. Copyright 2002 Massachusetts Medical Society

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A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

Wendy J Introne, Monique B Perry, James Troendle … (2011)

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis. Published by Elsevier Inc.

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Protein production: planet, profit, plus people?

Harry Aiking (2014)

Food sustainability and food security are increasingly in the spotlight and increasingly intertwined. According to some projections we will need to nearly double food production in the next 4 decades. This article argues that protein production and consumption are pivotal to sustainability, because anthropogenic contributions to the nitrogen cycle are 100-200% compared with a contribution of 1-2% to the carbon cycle by mineral fuel combustion, with biodiversity as the main casualty. Because 1 kg animal protein requires ∼ 6 kg plant protein, its large-scale production by means of factory farming is a major driver of biodiversity loss, climate change, and freshwater depletion. Furthermore, intensive livestock production is associated with antibiotics resistance and increasing incidence of emerging diseases. Therefore, a "reversed" diet transition back to less animal protein could make a difference. Some European countries, such as the United Kingdom, Sweden, and The Netherlands, have published integrated policy reports addressing food security, sustainability, and health combined. The food industry is focusing on food safety and increasingly on sustainability. An important issue is consumer communication, because consumer "framing" is radically different from that of governmental and industrial policy makers. There is no "one size fits all." A huge range of differences exists between countries and between distinct groups of consumers within countries; getting consumers to change their diets in a more sustainable direction is likely to require much more than gentle nudging. National governments and the United Nations should assume their responsibilities and initiate a global strategy integrating sustainability, food security, nutrition, and equity. To date, the profit pillar of sustainability has taken precedence over planet and people. It is time to redress the balance.

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Author and article information

Contributors

L. R. Ranganath: lrang@liv.ac.uk

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 27 September 2022

Publication date PMC-release: 27 September 2022

Publication date Collection: 2022

Volume: 12

Electronic Location Identifier: 16083

Affiliations

[1 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Departments of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, , Liverpool University Hospitals NHS Foundation Trusts, ; Prescot Street, Liverpool, L7 8XP UK

[2 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, William Henry Duncan Building, University of Liverpool, ; Liverpool, UK

[3 ]GRID grid.419303.c, ISNI 0000 0001 2180 9405, Biomedical Research Centre, , Slovak Academy of Sciences, ; Bratislava, Slovakia

[4 ]GRID grid.412134.1, ISNI 0000 0004 0593 9113, Hôpital Necker-Enfants Malades, ; Paris Cedex 15, France

[5 ]OnPoint Science AB, Stockholm, Sweden

[6 ]Garriguella AB, Ekerö, Sweden

Article

Publisher ID: 20424

DOI: 10.1038/s41598-022-20424-z

PMC ID: 9515198

PubMed ID: 36167967

SO-VID: 90db7494-97fe-4274-bf63-4bdf7a937312

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Date received : 22 March 2022

Date accepted : 13 September 2022

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ScienceOpen disciplines: Uncategorized

Keywords: biochemistry,chemical biology,physiology,diseases,molecular medicine,pathogenesis

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ScienceOpen disciplines: Uncategorized

Keywords: biochemistry, chemical biology, physiology, diseases, molecular medicine, pathogenesis

Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

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Most cited references 32

Natural history of alkaptonuria.

A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

Protein production: planet, profit, plus people?

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