Skip to main content

Table 1 Characteristics of included studies

From: Evaluation of pre-symptomatic nitisinone treatment on long-term outcomes in Tyrosinemia type 1 patients: a systematic review

Study Study design Participants Treatment
Birmingham cohort
 Bartlett 2014 [17] Prospective cohort
Follow-up time NR
Study setting: Birmingham Children’s Hospital, UK
Number of centres: 1
N = 38
TYR1 patients treated between 1989 and 2009.
Pre-NTBC: n = 7
Post-NTBC: n = 31
Age at presentation:
<2 months: n = 11
(6 detected by cascade testing,
4 incidental detection by routine PKU screening,
1 symptomatic presentation)
2–6 months: n = 11
>6 months: n = 9
Pre-NTBC: Diet
Post-NTBC: NTBC and diet.
NTBC: Initial dose of 1 mg/kg (0.6 mg/kg before 1995);
dose adjusted to clinical and biochemical response (including plasma and urinary SUAC) and plasma levels thereafter (target 50 μmol/l).
Diet NR
 McKiernan 2015 [14] Retrospective cohort
Age at last follow-up
Pre-clinically diagnosed: 3–12.5 years
Clinically diagnosed: 10–19 years or death at 1.5 and 7 months, respectively
Study setting: Birmingham Children’s Hospital, UK
Number of centres: 1
N = 17
TYR1 patients treated pre-symptomatically with NTBC following selective newborn screening and their clinically presenting siblings.
Pre-clinically diagnosed: n = 12
NTBC start: median 4 (range 2–52) days.
Clinically diagnosed siblings: n = 5
Age at presentation:
Median 4 (range 1.5–17) months.
NTBC and diet
NTBC: 1 mg/kg/day;
NTBC titrated according to body weight until 10 kg, after which adjusted according to blood NTBC concentrations (3 monthly assessments).
Diet: Fat soluble vitamin supplementation for at least 3 months.
Tyr and Phe restriction.
Breast feeding combined with Tyr and Phe free protein substitute.
For formula fed infants, Tyr and Phe free protein substitute with natural protein requirements supplied as conventional formula.
Dietary treatment titrated according to blood Phe and Tyr levels
(3 monthly assessments).
 Santra 2008 [12] Retrospective cohort
Follow-up: 1–10 years.
Study setting: Birmingham Children’s Hospital, UK
Number of centres: 1
N = 21
TYR1 patients treated with NTBC for at least 12 months.
Phenotype of liver disease at presentation:
Acute liver failure: n = 9
Age at presentation: Median 17 weeks
(range 1 month to 2 years).
Chronic liver disease: n = 7
Age at presentation: Median 60 weeks
(range 2 months to 9 years).
Pre-clinically: n = 5
Age at presentation: Median < 1 week
(range < 1 to 2 weeks).
NTBC and diet
NTBC: Standard protocol using nitisinone dosing of 0.6 mg/kg before 1995 and 1 mg/kg since 1995, the dose thereafter adjusted according to response.
Diet: Normocaloric Tyr- and Phe-restricted diet, fat-soluble vitamins in the presence of liver dysfunction and phosphate supplements during hypophosphataemia.
Québec cohort
 Larochelle 2012 [10] Cohort
(Before 1994 retrospective, thereafter prospective data collection)
Age at last follow-up (2009, death or OLT)
No NTBC: OLT/death at 0.5–10 years;
>30 days: 9–19 years or OLT/death at 2–8 years;
≤30 days: 5–11 years
(estimated by reviewers from bar chart)
Study setting: Québec, Canada
Number of centres: NR
N = 78
TYR1 patients born 1984–2004.
No NTBC: n = 28
(777 patient months)
NTBC introduced
≤30 days: n = 24
(all detected by routine TYR1 screening)
(2593 patient months).
>30 days: n = 26
(21/26 detected by routine TYR1 screening)
(535 patient months pre-NTBC;
3138 patient months with NTBC).
No NTBC: Diet (see below)
Early- and Late-NTBC: NTBC and diet
NTBC: Initially fixed at 0.6 or 1.0 mg/kg daily in 2 daily oral doses.
For the first 2 years of the study: recrystallized preparation of NTBC.
Thereafter: commercially-produced nitisinone.
After 1999: NTBC dose titrated in order to minimise urine SUAC levels.
Diet: Dietary restriction of Phe and Tyr aiming to maintain plasma Tyr at 200–400 μmol/L.
 Simoncelli 2015 [11] (supersedes Larochelle et al. [10]) Retrospective cohort
Follow-up until death or 1 January 2009;
Age at study end date (1 January 2009)
No NTBC: IQR 16.3–21.7 years
NTBC ≥4 weeks: IQR 12.6–15.0 years
NTBC <4 weeks: IQR 3.4–8.5 years
(p < 0.001, Kruskal-Wallis test)
Study setting: Québec, Canada
Number of centres: 5
N = 95
TYR1 patients treated between 1984 and 2008.
No NTBC: n = 28
NTBC introduced
<4 weeks: n = 41
Median 13 days (IQR 11–16 days)
(all detected by routine TYR1 screening).
≥4 weeks: n = 26
Median 1.0 years (IQR 0.4–2.2 years)
(21/26 detected by routine TYR1 screening)
No NTBC: Diet and “curative” OLT.
Early- and Late-NTBC: NTBC and diet.
(NR, possibly as in Larochelle et al. [7])
International studies
 Mayorandan 2014 [18] Retrospective cohort
(Retrospective data collected via questionnaire)
Average follow-up time: 9.1 (SD 6.3) years.
Study setting: Europe, Turkey and Israel.
Number of centres: 21
N = 168 included in study.
TYR1 patients with questionnaire data.
No NTBC: n = 10
NTBC: n = 154 (1157 patient years)
No data on treatment: n = 4
N = 148 NTBC-treated patients included in analysis:
NTBC start:
<1 month: n = 37
(unclear if detected following screening or symptomatically)
1–6 months: n = 45
7–12 months: n = 20
>12 months: n = 46
Varying NTBC and diet treatment strategies between different centres.
NTBC (n = 154):
Initial NTBC dosage:
Mean 1.7 mg/kg/day (SD 0.5, range 0.2–5)
Current maintenance therapy:
Mean 1.0 mg/kg/day (SD 0.3, range 0.3–2)
1–3 doses per day, on average 2 doses per day.
Diet: All patients received dietary treatment in addition to NTBC.
Natural protein restriction or Phe and Tyr calculation in 38%, natural protein restriction or Tyr intake calculation in 19%, natural protein restriction only in 19%, and Tyr and Phe calculation in 24% of centres.
 Van Ginkel 2016 [19] Cross-sectional
(retrospective and prospective data collection)
Study setting: Netherlands, Belgium, UK
Number of centres: NR (multicentre)
N = 38 included in study
19 TYR1 patients and 19 age- and gender matched healthy controls.
Included in subgroup analysis:
N = 17–19 TYR1 patients
Age at diagnosis
<2 months (pre-symptomatically): n = 8–10
(detected by cascade testing or as coincidence in routine PKU screening)
2–6 months: n = 6
>6 months: n = 3
NTBC and diet
Varying NTBC and diet treatment strategies between different centres.
Diet: Phe and Tyr restricted.
Natural protein restriction.
Supplementation of all non-Phe and non-Tyr amino acids provided with one of the available amino acid mixtures that contain neither Phe nor Tyr.
  1. IQR interquartile range, NR not reported, NTBC 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, nitisinone, OLT, orthotopic liver transplantation, Phe phenylalanine, PKU phenylketonuria, SD standard deviation, SUAC succinylacetone, Tyr tyrosine, TYR1 Tyrosinemia type 1