Background
Methods
Search strategy
Eligibility
Study selection and data extraction
Quality appraisal
Data summary and synthesis
Results
Searching, sifting, and sorting
Characteristics of included studies
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 (sibling-controlled) 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. |
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. |
Quality appraisal
Study | Global rating from sections A-F | Global rating for this study | |||||
---|---|---|---|---|---|---|---|
A) Selection bias | B) Study design | C) Confounders | D) Blinding | E) Data collection methods | F) Withdrawals and drop-outs | ||
Québec study | |||||||
Larochelle 2012 [10] | Strong | Moderate | Weak | Moderate | Strong | Strong | Moderate |
Simoncelli 2015 [11] | Strong | Moderate | Weak | Moderate | Strong | Strong | Moderate |
Birmingham study | |||||||
Bartlett 2014 [17] | Strong | Moderate | Weak | Moderate | Strong | Strong | Moderate |
McKiernan 2015 [14] | Weak | Moderate | Weak | Moderate | Weak | Strong | Weak |
Santra 2008 [12] | Moderate | Moderate | Weak | Moderate | Weak | Weak | Weak |
International cohort | |||||||
Mayorandan 2014 [18] | Weak | Moderate | Weak | Moderate | Weak | Strong | Weak |
Cross-sectional study | |||||||
Van Ginkel 2016 [19] | Weak | Weak | Weak | Moderate | Strong | Strong | Weak |
Mortality rate
Hepatic manifestations of TYR1 and requirement for liver transplantation
Study | Study design | Participants | Outcome | Age at last follow-up / study end date | |
---|---|---|---|---|---|
Birmingham study | |||||
Bartlett 2014 [17] | Cohort (prospective data collection) | N=38 No NTBC: n=7 NTBC: n=31 Age at presentation: <2 months: n=11 2-6 months: n=11 >6 months: n=9 |
OLT
| ||
<2 months: | 0/11 | NR | |||
2-6 months: | 3/11 (27%) | NR | |||
>6 months: | 4/9 (44%) | NR | |||
No NTBC: | 6/7 (86%) | NR | |||
(p=0.004 vs 7/31 with NTBC) | |||||
Median age at NTBC start No OLT: 52 (range 2-990) days; OLT: 428 (range 86-821) days. (p=0.004) | |||||
McKiernan 2015 [14] | Cohort (sibling-controlled, retrospective data collection) | N=17 Pre-clinically diagnosed: n=12 Clinically diagnosed siblings: n=5 |
OLT
| ||
Pre-clinically: | 0/12 | 3-12.5 years; | |||
Clinically: | 1/5 (20%) | 10-19 years or death at 1.5 and 7 months, respectively | |||
Liver disease
| |||||
Pre-clinically | 0/12 | 3-12.5 years; | |||
Clinically | 2/3 (67%) surviving patients | 10-19 years | |||
Québec study | |||||
Larochelle 2012 [10] | Cohort (Before 1994 retrospective, thereafter prospective data collection) | N=78 NTBC introduced ≤30 days: n=24 >30 days: n=26 No NTBC: n=28 |
UI
| ||
≤30 days: | 0/24 | 5-11 years; | |||
>30 days: | 7/26 (27%) | 9-19 years or OLT/death at 2-8 years; | |||
No NTBC: | 20/28 (71%) | OLT/death at 0.5-10 years | |||
p < 0.001, ≤30 days vs No NTBC (Chi square test); p < 0.001, >30 days vs No NTBC (Chi square test); p = 0.010, ≤30 vs >30 days (Fisher exact test)a
| |||||
Simoncelli 2015 [11] | Cohort (Retrospective data collection) | N=95 <4 weeks: n=41 ≥4 weeks: n=26 No NTBC: n=28 Supersedes Larochelle et al. [10] |
OLT
| ||
<4 weeks: | 0/41 | IQR 3.4-8.5 years | |||
≥4 weeks: | 7/26 (27%) | IQR 12.6-15.0 years | |||
No NTBC: | 20/28 (71%) | IQR 16.3-21.7 years | |||
(p<0.001, Fisher exact test) | (p<0.001, Kruskal-Wallis test) | ||||
International cohort | |||||
Mayorandan 2014 [18] | International cohort (retrospective data collection via questionnaire) | N=168 included in study. N=148 NTBC-treated patients included in analysis. NTBC start: <1 month: n=37 1-6 months: n=45 7-12 months: n=20 >12 months: n=46 |
OLT
| OR (95%CI) | |
>12 months: | 12.7 (1.5-103)b
| NR | |||
Acute liver disease
| |||||
<1 month: | 0/37 | NR | |||
7-12 months: | 3/20 (15%)* | NR | |||
Liver cancer
| OR (95%CI) | ||||
>12 months: | 12.7 (1.5-103)b
| NR | |||
Liver cirrhosis
| OR (95%CI) | ||||
7-12 months: | 41.6 (2.2-779.9)b
| NR | |||
>12 months: | 40.5 (2.3-704.1)b
| NR | |||
Hepatomegaly
| OR (95%CI) | ||||
1-6 months: | 3.3 (0.9-11.3)b
| NR | |||
7-12 months: | 4.4 (1.1-17.7)b
| NR | |||
>12 months: | 3.9 (1.1-13.3)b
| NR | |||
Odds/rates for not presented late-treated groups were not significantly different compared to early NTBC (<1 month). |
Renal dysfunction and rickets
Hospital admissions
Neurocognitive outcomes
Post hoc comparisons
1) screen detected vs symptomatically detected patients, direct nitisinone start after diagnosis
Death | Need for OLT | Patients with neurological crisis | |
---|---|---|---|
Initial analysis
Early vs late |
Québec cohort
Larochelle 2012 [10] 0/24 vs 2/26 (p = 0.49)a
Birmingham study McKiernan 2015 [14] 0/12 vs 2/5 (p = 0.07)
|
Québec cohort
Larochelle 2012 [10] 0/24 vs 7/26 (p = 0.01)a
Birmingham study
McKiernan 2015 [14] 0/12 vs 1/5 (p = 0.29)
Bartlett 2014 [17] 0/11 vs 7/20 (p = 0.033)
|
Québec cohort
Larochelle 2012 [10] 0/24 vs 5/26 (p = 0.051)
Simoncelli 2015 [11] 0/41 vs 5/26 (p = 0.007)
|
Post hoc 1
Screen detection vs symptomatic detection, all with direct nitisinone initiation |
Québec cohort
Larochelle 2012 [10] 0/24 vs 0/5
Birmingham study McKiernan 2015 [14] 0/12 vs 1/4 (p = 0.25)
|
Québec cohort
Larochelle 2012 [10] 0/24 vs 3/5
(p = 0.0027)
Birmingham study McKiernan 2015 [14] 0/12 vs 1/4 (p = 0.25)
Bartlett 2014 [17] 0/10 vs 5/15 (p = 0.061)
|
Québec cohort
Larochelle 2012 [10] 0/24 vs 0/5 Simoncelli 2012 [11] NA |
Post hoc 2
Early symptomatic vs late symptomatic,all with direct nitisinone initiation |
Québec cohort
Larochelle 2012 [10] NA
Birmingham cohort
NA |
Québec cohort
Larochelle 2012 [10] NA
Birmingham cohort McKiernan 2015 [14] NA Bartlett 2014 [17] 0/1 vs 5/14 |
Québec cohort
NA |
Post hoc 3
Screen detection, direct nitisinone initiation vs screen detection, 1–12 months delayed nitisinone initiation |
Québec cohort
Larochelle 2012 [10] 0/24 vs 0/10
Birmingham cohort
NA |
Québec cohort
Larochelle 2012 [10] 0/24 vs 0/10
Birmingham cohort McKiernan 2015 [14] NA Bartlett 2014 [17] NA |
Québec cohort
Larochelle 2012 [10] 0/24 vs 1/10 (p = 0.294)
Simoncelli 2015 [11] NA |