Biliary atresia: neurodevelopment and quality of life
Rodijk, Lyan
DOI:
10.33612/diss.133865199
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Publication date:
2020
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Rodijk, L. (2020). Biliary atresia: neurodevelopment and quality of life. University of Groningen.
https://doi.org/10.33612/diss.133865199
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Chapter 2
Chapter 2
Journal of Pediatric Gastroenterology and Nutrition. 2018;67:157-168.
Neurodevelopmental
outcomes in children
with liver diseases:
a systematic review
Journal of Pediatric Gastroenterology and Nutrition. 2018;67:157-168. Lyan H. Rodijk, Anne E. den Heijer, Jan B.F. Hulscher, Henkjan J. Verkade, Ruben H. de Kleine, Janneke L.M. Bruggink
Abstract
ObjectiveThe aim of this study was to determine the neurodevelopmental outcomes of children with a liver disease based on a systematical review of the literature.
Method
A literature search according to the PRISMA statement was conducted using predefined search terms in PubMed, Cochrane Library, and PsycINFO. The inclusion criterion was studies published from 2000 onwards that reported on the neurodevelopmental outcomes of term-born children with liver diseases. A narrative synthesis was done to appraise the studies.
Results
Twenty-five studies were included (1913 children), 19 of which described children after liver transplantation (LTx; 1372 children). Sixty-seven percent of the studies on children with liver diseases who survived with their native livers showed low-average or abnormal scores on specific subscales of cognitive and behavioral measures. In studies on children after LTx, this was 82%. After LTx, 83% of studies demonstrated impaired outcomes on behavior, while 42% of children received special education. Motor development was impaired in 82% of studies in children with native liver and after LTx.
Limitations
Studies were heterogenic due to sample sizes, etiology of liver disease and type of assessment tools used.
Conclusions
More than two-third of the included studies showed neurodevelopmental deficits in children with a liver disease, affecting all neurodevelopmental areas. Knowledge on risk factors for impaired neurodevelopment is limited and lack of long term follow-up is worrying, especially considering the increasing survival rates, resulting in more at-risk patients. Studying early predictors and at-risk factors of abnormal developmental trajectories of children with a liver disease is indicated to assess strategies to improve their long-term neurodevelopmental outcomes.
Introduction
The structural morphology of the brain is well-established at birth, while vital functional
maturation continues postnatally.1 Intellectual functioning and motor development
develops rapidly during the first years of life and this maturation is influenced by
neuronal input, such as environmental and experiential factors.1 Nevertheless, several
pediatric patient groups are known to be at risk of neurodevelopmental delays during this period. Early risk factors for neurodevelopmental delays in children include preterm birth and subsequent intensive neonatal care, complications during birth, infections, unconjugated hyperbilirubinemia, anesthesia, major surgery, malnutrition,
growth restriction, and environmental deprivation.2–5 Accordingly, severe disease,
hospitalization, and surgery during early childhood are also thought to interfere with the healthy development of children’s central nervous systems.
Infants with congenital liver diseases are often exposed to one or more of the above risk factors. Previous studies primarily explored the influence of liver transplantation
(LTx) on neurodevelopmental outcomes.6–9. The outcomes, however, of children with
liver diseases prior to LTx might already be impaired due to existing morbidities.3,9,10
To date, the exact interaction or role of risk factors on neurodevelopment is not yet fully delineated. As survival rates are increasing, it is essential to explore the possible adverse consequences of early liver diseases, in order to grow up to productive, independent young adults.
Our aim was:
• to determine the neurodevelopmental outcomes of children with liver diseases
based on a systematical review of the literature.
• to identify neurodevelopmental deficits and related risk factors in children
with liver diseases, both in children with liver diseases who survived with their native livers and after LTx, in order to identify fields of neurodevelopment that are most affected and that could possibly benefit from intervention programs at an early stage.
Methods
The study protocol was registered with PROSPERO, the international prospective register of systematic reviews, under number CRD42016039074. Studies on the neurodevelopmental outcomes in children with liver diseases were retrieved from PubMed, the Cochrane database, and PsycINFO from January 1, 2000 until March
31, 2017 and a structured literature search was performed according to the PRISMA statement. The following predefined search terms were used: infant, newborn, child, youth; liver disease, liver failure; cognition disorders, psychomotor disorders, problem behavior, neurodevelopment, developmental outcome, learning disorder, IQ, motor outcome, neuropsychology, psychomotor, and the different etiologies of liver diseases, as described in our research protocol.
All articles were screened independently and blindly by three authors (LHR, JLB, and AEDH). Firstly, one author (LHR) screened all articles on title and abstract. Similarly, the other two authors (JLB and AEDH) both blindly screened half of the articles. After the initial search, duplicates and articles published before 2000 were excluded and articles were screened on title and abstract. In case of a discrepancy the three authors discussed the matter until consensus was reached. In addition to the articles found through the literature search, the reference lists of the included studies were examined to identify possible additional studies eligible for inclusion.
Inclusion criteria were studies that reported on liver diseases in childhood and described neurodevelopmental outcomes of children with respect to cognition, social-emotional, behavioral and motor functions were included. Only studies that used standardized tests or validated questionnaires were included. Studies eligible for inclusion described term-born children aged between 0 and 18 years. Exclusion criteria were articles not written in English, or when they did not match domain, determinant or outcome, i.e. when they did not use standardized tests or validated questionnaires. Studies that did not describe the etiology of liver diseases were also excluded. All types of study designs were included, except reviews, case series and case reports on fewer than ten cases, abstracts, posters, and books.
A narrative synthesis was conducted and the following data extracted from the included articles: study design, duration of follow-up, types of liver disease, patient characteristics, assessment tools, neurodevelopmental domains, cognitive, behavioral and motor outcomes, and possible risk factors for neurodevelopmental impairments. Also, data on school performance was extracted from the articles. In order to obtain a clear overview of the differences between studies in children with their native livers and studies in children after LTx, these studies were displayed separately. In LTx studies age at LTx, duration of follow-up after LTx, and whether the donor liver came from a living or a deceased donor was also included.
Table 1 and 2 display information on the included studies: study design; participants; etiology of liver disease; used assessment tools; cognitive, behavioral and/or motor outcomes and risk factors for impaired neurodevelopmental outcomes. When classifying in borderline and abnormal neurodevelopmental scores, included studies used cut-off values following the criteria of test manuals (e.g. for the WISC, cut-off values for IQ were < 85 for borderline IQ (-1SD) and < 70 for abnormal IQ (-2SD)).
Results
Figure 1 shows the inclusion chart. After literature search 1276 related publications were included. Ultimately, upon analysis of eligibility, 25 papers were included amounting to 1913 patients with liver diseases, of whom 541 not-transplanted and 1372 transplanted children. Table 1 and 2 provide a detailed overview of the included studies.
All studies described neurodevelopmental outcomes in children with liver diseases of different underlying etiologies. Nineteen of these studies were on children after LTx. The children who participated in the various studies represented a heterogeneous group of liver diseases, such as viral hepatitis, metabolic etiologies, biliary atresia, and liver tumors. The number of patients varied between 11 and 823 children. Control groups were used in 11 studies.
All of the used test batteries and questionnaires were validated and internationally accepted. There was a high diversity in used test batteries and questionnaires, all displayed in Table 1 and 2. To assess cognition, mostly used were versions of the Wechsler Intelligence Scales (WISC), i.e. in 14/23 studies, according to different age categories. For behavioral outcome and executive function the following assessments were predominantly used: Child Behavior Checklist (CBCL) in 4/13 studies and Behavior Rating Inventory of Executive Function (BRIEF) in 6/13 studies respectively. Motor outcome was assessed with Mullen Scales of Early Learning (MSEL) in both studies assessing motor outcomes in children with native liver disease. In children after LTx, the most used test was the movement ABC.
The neurodevelopmental outcomes of children with liver diseases who still had their native liver
Table 1 provides an overview of the neurodevelopmental outcomes of children with liver disease who still had their native livers. In children with viral hepatitis and hepatic encephalopathy due to acute liver failure, significantly lower scores on cognition tests were observed, both in acute and under more chronic conditions (IQ (mean ±
SD) 61.8 ± 13.6 in children with chronic viral hepatitis vs 106.2 ± 12.8 in controls).11,12 The
results of children with acute liver failure normalized during follow-up, approximately
five months after discharge, when the hepatic encephalopathy resolved.11 Children
suffering from chronic viral hepatitis, with normal liver function tests, obtained lower scores on vocabulary, total verbal relation, the bead memory test, total short-term
memory, and IQ, in comparison to healthy controls.12 In other studies, children with
viral hepatitis showed neither impaired outcomes on cognitive tests, nor differences in behavioral outcomes in comparison to the norm population or uninfected controls
(i.e. IQ mean 103.9).13,14
In children with biliary atresia (BA), who were being evaluated for LTx, lower scores on cognitive outcomes were reported in comparison to the norm population (visual reception 89.90 ± 8.42, expressive language 90.60 ± 19.91, receptive language 79.90
± 13.25 compared to norm scores with a mean of 100).10,15 Motor development was
also impaired in children with BA (gross motor 71.80 ± 13.14, fine motor 94.53 ± 19.80
compared to norm scores with a mean of 100).10,15 Thus far, no studies have been
published on behavioral outcomes in children with BA, without LTx.
School performance (percentage special education or repeated classes) was not reported in studies on children with liver diseases who still had their native livers.
The neurodevelopmental outcomes of children after liver transplantation
Table 2 provides an overview of the studies on the neurodevelopmental outcomes of children with liver diseases after LTx. In most studies on children after LTx, intelligence scores were below the average of the norm population, but still fell within the average
range (i.e. FSIQ 86.6-98).9,16–24 Kaller and colleagues found that all scores on cognition
abilities fell in the low-average range in children at least one year after LTx. Almost 10% of these children had an abnormal total IQ (<70) in comparison to 4.7% of their healthy peers. Furthermore, 16% of children with liver diseases scored within the borderline
IQ range (70-84) in comparison to 6% of their healthy peers.18 In the subcategories
of the cognitive tests, such as attention abilities, executive functioning, visuospatial functioning, and language development, the mean scores fell within the average
range, but below the population mean (Table 1 and 2).6–8,15,17,19,20,23,25,26 Moreover,
Sorensen and colleagues found no improvement in cognition after LTx, only reading
was likely to improve.20 Stevenson and colleagues found, in their longitudinal cohort,
impaired cognitive outcomes pre-LTx and a significant decrease at three months
post-LTx.9 At one year post-LTx the scores had returned to the pre-LTx level with no
further improvement at two years after LTx.9
Children receiving LTx for liver diseases showed more total behavioral (12% borderline scores, 32-50% abnormal) and externalizing problems (4-31% borderline scores, 32-31% abnormal) in comparison to the norm population or in comparison to children with
stable chronic liver diseases.7,19,27
Motor outcomes were impaired in children with LTx in comparison to healthy
children.6,28 Almaas and colleagues found in their longitudinal cohort with 4 year
follow-up no improvement in motor scores with time after transplantation.28 In
contrast, Van Mourik and colleagues found that individual motor scores improved
gradually after LTx and reached the average range within four years after LTx.29
In metabolic patients, psychomotor functions were delayed at -2 SD before
transplantation.9 The scores of patients who had received a transplant at less than
42 months of age, improved over 2 years of time to the low-average range.9
School performance was reported in 8/19 studies on children with liver disease and LTx. Of included children, up to 42% needed special education and 6-55% had
repeated one or more classes at school (Table 2).8,9,16,19,22,23,30,31
Children with liver diseases before or after LTx show impairments on all domains of neurodevelopment in comparison to the general pediatric population. Although the mean subscores often fall within the average range, the shift in distribution to lower scores implies that a larger fraction of children have abnormal scores at individual level.
Risk factors associated with neurodevelopmental outcomes
In Table 1 and 2 an overview is provided of risk factors for neurodevelopmental impairments in children with liver diseases. Cognitive outcomes in children with liver diseases before and after LTx were negatively correlated with low weight and height
z- scores at the time of surgery (Kasai Hepato-portoenterostomy or LTx) 8,10,15,20,21,26, age
at LTx, blood transfusion volume during LTx, days spent in hospital less than one year
post-LTx, and number of pre-LTx, peri-LTx, and post-LTx complications. 7,8,17,20,26 Also, in a
multi-center study, one-person households were associated with impaired cognitive
outcomes.20 Some studies performed multiple regression analysis and reported
higher scores on late postoperative (between three and ten years) achievement scales in patients who had a living-related donor in comparison to a cadaveric
organ.8,26 In children with viral hepatitis and hepatic encephalopathy due to acute
liver failure, cognitive test results were negatively correlated to elevated blood
pro-inflammatory cytokines and liver changes on MRI.11,12 Furthermore, more impaired
scores on cognition were reported in children after LTx for genetic-metabolic induced liver disease in comparison to children after LTx with BA or other cholestatic diseases,
both before LTx and during follow-up.9,18,21
Risk factors for impaired motor outcomes in children with liver diseases were impaired
nutritional status peri-LTx, shorter disease period before LTx, and LTx at older ages. 23,29
Concerning school performance, the most striking risk factor for special education
post-LTx was requirement for special education pre-LTx.31 Use of calcineurin inhibitors
or cyclosporine/other non-calcineurin inhibitor based immunosuppression was
associated with impaired scores on cognition and special education.21,31
Ta bl e 1 . N eur od ev elo pm en t in c hil dr en w ith li ver d is ea se w ho s til l ha d t he ir na tiv e li ver s. Au th ors Year St ud y des ig n Pa rt ic ip ants Ag e r an ge y ; n; % b oy s; c on tr ol s Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or c on tr ol gr oup s Ri sk f ac to rs Ab u F adda n 201 5 C ro ss -sec tio nal 3 – 1 8 y n = 3 5; 8 0% b oy s He al th y c ontr ol s: n = 2 3 HCV SB 4 C : ↓ IQ , v oc ab ul ar y, c ompr eh en si on , ab st ra ct v is ual rea so ning , q uan tit at iv e rea so ning , bea d m em or y, to tal s ho rt -te rm m em or y = t ot al v er ba l r el at io n, m em or y f or se nt en ces C : C yt ok ine d ys re gu la tion (m ea su re d b y I FN A a nd I L 6 ) d ue to l iv er f ai lu re C audl e 201 2 C ro ss -sec tio nal Pr e-Lt x 3 - 2 0 m on th s n = 3 3; 3 6% b oy s BA M SEL C : ↓ e xpr es si ve and rec ep tiv e l ang ua ge G irls: ↓ v is ual rec ep tio n, rec ep tiv e lang ua ge and e xpr es si ve lang ua ge Bo ys : ↓ e xpr es si ve lang ua ge M : ↓ g ro ss m ot or sk ills C : L ow er w ei gh t and h ei gh t z sc or es p re -L Tx ; o ld er a t K as ai (bo th bo ys and g irl s) G irl s: e le va ted s er um C -b ilir ub in le ve ls M : e le va te d I N R Sr iva st ava 201 2 Lo ng i-tud inal FU : < 1 y M ean a ge : 7.8 ± 2 .7 y n = 1 1; 4 5% b oy s He al th y c ontr ol s: n = 8 AL F/ vir al h epa tit is 7/ 11 H AV 1/1 1 H BV 3/ 11 c o-in fe ct ed w ith HAV /H EV RA KI T a t T 2 a nd T 3 C: T1: ↓ (8 /9 te st s) T2 : ↓ (2 /9 t es ts , r es t n or m al ize d) C : E le vat ed b lo od p ro -in fla m m at or y c yt ok in es a nd l os s of v ol um e o f m amm ill ar y bo di es du e t o l iv er f ai lu re C audl e 201 0 C ro ss -sec tio nal Pr e-LTx 4 – 2 1 m on th s n = 1 5; 7 % b oy s BA M SEL C : ↓ v is ual re cep tio n, lang ua ge s ub sc al es M : ↓ fi ne a nd g ro ss m ot or s ki lls C : O ld er a t K as ai a nd l ow er w ei gh t z s co re p re -LTx M : M or e s ev er e l iv er d is ea se (m ea su re d b y I N R) Rodr ig ue 20 09 C ro ss -sec tio nal M ea n a ge : 11±3 SD y n = 1 14 ; 5 5% b oy s Pr e-tr an sp la nt samp le n = 6 7 HCV BR IEF CB CL C D I C : = (norm s) ↑ in iti at io n and w or king m em or y ( pr e-tr an sp lan t s amp le ) B: = N ot repo rt ed
Ta bl e 1 . N eur od ev elo pm en t in c hil dr en w ith li ver d is ea se w ho s til l ha d t he ir na tiv e li ver s. Au th ors Year St ud y des ig n Pa rt ic ip ants Ag e r an ge y ; n; % b oy s; c on tr ol s Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or c on tr ol gr oup s Ri sk f ac to rs Ab u F adda n 201 5 C ro ss -sec tio nal 3 – 1 8 y n = 3 5; 8 0% b oy s He al th y c ontr ol s: n = 2 3 HCV SB 4 C : ↓ IQ , v oc ab ul ar y, c ompr eh en si on , ab st ra ct v is ual rea so ning , q uan tit at iv e rea so ning , bea d m em or y, to tal s ho rt -te rm m em or y = t ot al v er ba l r el at io n, m em or y f or se nt en ces C : C yt ok ine d ys re gu la tion (m ea su re d b y I FN A a nd I L 6 ) d ue to l iv er f ai lu re C audl e 201 2 C ro ss -sec tio nal Pr e-Lt x 3 - 2 0 m on th s n = 3 3; 3 6% b oy s BA M SEL C : ↓ e xpr es si ve and rec ep tiv e l ang ua ge G irls: ↓ v is ual rec ep tio n, rec ep tiv e lang ua ge and e xpr es si ve lang ua ge Bo ys : ↓ e xpr es si ve lang ua ge M : ↓ g ro ss m ot or sk ills C : L ow er w ei gh t and h ei gh t z sc or es p re -L Tx ; o ld er a t K as ai (bo th bo ys and g irl s) G irl s: e le va ted s er um C -b ilir ub in le ve ls M : e le va te d I N R Sr iva st ava 201 2 Lo ng i-tud inal FU : < 1 y M ean a ge : 7.8 ± 2 .7 y n = 1 1; 4 5% b oy s He al th y c ontr ol s: n = 8 AL F/ vir al h epa tit is 7/ 11 H AV 1/1 1 H BV 3/ 11 c o-in fe ct ed w ith HAV /H EV RA KI T a t T 2 a nd T 3 C: T1: ↓ (8 /9 te st s) T2 : ↓ (2 /9 t es ts , r es t n or m al ize d) C : E le vat ed b lo od p ro -in fla m m at or y c yt ok in es a nd l os of v ol um e o f m amm ill ar y bo di es du e t o l iv er f ai lu re C audl e 201 0 C ro ss -sec tio nal Pr e-LTx 4 – 2 1 m on th s n = 1 5; 7 % b oy s BA M SEL C : ↓ v is ual re cep tio n, lang ua ge s ub sc al es M : ↓ fi ne a nd g ro ss m ot or s ki lls C : O ld er a t K as ai a nd l ow er w ei gh t z s co re p re -LTx M : M or e s ev er e l iv er d is ea se (m ea su re d b y I N R) Rodr ig ue 20 09 C ro ss -sec tio nal M ea n a ge : 11±3 SD y n = 1 14 ; 5 5% b oy s Pr e-tr an sp la nt samp le n = 6 7 HCV BR IEF CB CL C D I C : = (norm s) ↑ in iti at io n and w or king m em or y ( pr e-tr an sp lan t s amp le ) B: = N ot repo rt ed Ta bl e 1 . C onti nu ed . Au th ors Year St ud y des ig n Pa rt ic ip ants Ag e r an ge y ; n; % b oy s; c on tr ol s Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or c on tr ol gr oup s Ri sk f ac to rs So og oor 20 06 C ro ss -sec tio nal 6 – 1 9 y HC V: n = 1 26 HC V/ H IV : n = 2 07 % b oy s: N R Sib ling s: n = 4 7 HC V HC V/ H IV VA BS W AI S W IS C -R C: ↑ I Q , v oc ab ul ar y (H C V v er su s u nin fec ted gr ou p) B: ↓ ¼ s ub sc al es (d ual ly in fec ted gr ou p) = ( HC V and u nin fec ted ) N ot repo rt ed ↑ hi gh s cor es /si gn ific an tly h ig he r t ha n norm s or c on tr ol g ro up s; = a ve ra ge s cor es /no si gn ific an t d iff er enc e w ith norm s or c on tr ol g ro up s; ↓ /= l ow -a ve ra ge s co re s; ↓ l ow s co res si gn ifi ca nt ly lo w er th an no rm s or co nt ro l g ro up s. FU , f ol lo w -u p; T1 , T im e po in t 1 ; T 2, Ti m e po in t 2 ; y , y ea r. C, co gn iti ve o ut co m es , M, m ot or o ut com es ; B, behav io ral o ut co m es . A LF ac ut e l iv er f ai lu re ; B A , b ili ar y a tr es ia ; H AV , h ep at iti s A ; H BV , h ep at iti s B ; H C V, h ep at iti s C ; H EV , h ep at iti s E ; L Tx , li ve r t ra ns pl an ta tio n. As se ss m en t t ool s: B RI EF , B ehav io r R at ing In ven to ry o f E xec ut iv e F un ct io n; C BC L, C hil d B ehav io r C hec kli st ; C D I, C hil dr en ’s D epr es si on In ven to ry; M SE L, M ul len S cale s o f E ar ly Lear ning RA KI T, Th e Re vi sed A m st er dam se K inder In te lli gen tie te st ; S B4 , S tan fo rd -B in et In te lli gen ce S cal e: fo ur th ed iti on ; V AB S, V in el and A dap tiv e Behav io r S cal e; W AI S-R, W ec hsl er A du In te lli ge nc e S ca le – R ev is ed ; W IS C , W ec hs le r I nt el lig en ce S ca le f or C hi ld re n.
2
Ta bl e 2 . N eur od ev elo pm en t in c hil dr en w ith li ver d is ea se and LT x. Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs G ol d 201 7 C ro ss -sec tio nal Pr e-LTx (2 8% ) and post -LTx (7 2%) 3 – 7 y n = 1 8; 3 3% bo ys Ch ro ni c c hole st at ic liv er di se ase ; 17 /1 8 B A 1/1 8 A 1A T ( N L) BAS C -I I BV M I BR IE F M -A BC Vind el and -I I WPP SI -I V C: = B: P ar en tal repo rt s: LT x ↓ ina tt en tio n, com m un ic at ion , s oc ia l a bi lit ie s ( ve rs us N L) Teach er s < par en ts M : = ↓ vi su al b as ed d iffi cu lti es Par en tal repo rt s: LT x ↓ (v er su s N L) B, M : L Tx i n i nf an cy o r e ar ly ch ild hoo d. Alma as 201 5 Lo ng i-tud inal FU : 4 y Po st -LTx 4 – 1 2 y n = 3 5; 5 2% b oy s He al th y c ontr ol s: n = 3 87 16 /3 5 B A 4/ 35 A ag ena es s yndr om e 4/ 35 L iv er t um or 3/ 35 ALF 3/ 35 N eon at al c ho le st asis 2/ 35 A 1AT 1/3 5 Al ag ille 1/3 5 T yr osi ne mi a 1/3 5 P V T M -A BC M : ↓ + 4 y : ↓ ↓ bal l s co re s c omp ar ed to 1 st as se ssme nt N ot repo rt ed So ren sen 201 5 C ro ss -sec tio nal Pr e-LTx (3 6% ) and post -LTx (6 4% ) 6 – 1 6 y n = 3 6; 5 0% b oy s ALF 3/36 A ce ta mi nop he n t ox ic ity 4/ 36 A ut oimm un e d is ea se 4/ 36 M et abo lic d is or der s 3/ 36 V iral in fec tio n 17 /3 6 I nd et er m ina te 5/ 36 O th er BV M I-6 W IS C -I V C PT -2 BR IEF C D I-2 C : = ↓ ( 1/5 s ub te st s o f a tt en tio n) B: S el f-re po rt s: = Par en tal repo rt s: ↓ in hi bit ion = e xe cut iv e f unc tion s, m et ac og nit ion Tea ch er repo rt s: ↓ in hi bit ion , e xe cut iv e fu nc tion s, m et ac og nit ion M : ↓ m ot or c oor di na tion , v is ua l per cep tio n = v is ual m ot or in tegr at io n ↑ vi su al sp at ia l a bili ty N ot repo rt ed
Ta bl e 2 . N eur od ev elo pm en t in c hil dr en w ith li ver d is ea se and LT x. Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs G ol d 201 7 C ro ss -sec tio nal Pr e-LTx (2 8% ) and post -LTx (7 2%) 3 – 7 y n = 1 8; 3 3% bo ys Ch ro ni c c hole st at ic liv er di se ase ; 17 /1 8 B A 1/1 8 A 1A T ( N L) BAS C -I I BV M I BR IE F M -A BC Vind el and -I I WPP SI -I V C: = B: P ar en tal repo rt s: LT x ↓ ina tt en tio n, com m un ic at ion , s oc ia l a bi lit ie s ( ve rs us N L) Teach er s < par en ts M : = ↓ vi su al b as ed d iffi cu lti es Par en tal repo rt s: LT x ↓ (v er su s N L) B, M : L Tx i n i nf an cy o r e ar ly ch ild hoo d. Alma as 201 5 Lo ng i-tud inal FU : 4 y Po st -LTx 4 – 1 2 y n = 3 5; 5 2% b oy s He al th y c ontr ol s: n = 3 87 16 /3 5 B A 4/ 35 A ag ena es s yndr om e 4/ 35 L iv er t um or 3/ 35 ALF 3/ 35 N eon at al c ho le st asis 2/ 35 A 1AT 1/3 5 Al ag ille 1/3 5 T yr osi ne mi a 1/3 5 P V T M -A BC M : ↓ + 4 y : ↓ ↓ bal l s co re s c omp ar ed to 1 st as se ssme nt N ot repo rt ed So ren sen 201 5 C ro ss -sec tio nal Pr e-LTx (3 6% ) and post -LTx (6 4% ) 6 – 1 6 y n = 3 6; 5 0% b oy s ALF 3/36 A ce ta mi nop he n t ox ic ity 4/ 36 A ut oimm un e d is ea se 4/ 36 M et abo lic d is or der s 3/ 36 V iral in fec tio n 17 /3 6 I nd et er m ina te 5/ 36 O th er BV M I-6 W IS C -I V C PT -2 BR IEF C D I-2 C : = ↓ ( 1/5 s ub te st s o f a tt en tio n) B: S el f-re po rt s: = Par en tal repo rt s: ↓ in hi bit ion = e xe cut iv e f unc tion s, m et ac og nit ion Tea ch er repo rt s: ↓ in hi bit ion , e xe cut iv e fu nc tion s, m et ac og nit ion M : ↓ m ot or c oor di na tion , v is ua l per cep tio n = v is ual m ot or in tegr at io n ↑ vi su al sp at ia l a bili ty N ot repo rt ed Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs So ren sen 201 4 Lo ng i-tud inal FU : 3 y Po st -LTx 5 – 9 y T1: n = 1 44 T2 : n = 9 3 47 % b oy s 56 /9 3 BA 8/ 93 A LF 13 /9 3 O th er c hole st at ic liv er di se ase s 8/ 93 M et abo lic d is or der s 8/ 93 O th er W IS C -I V W RAT -4 BR IEF SA AP S C : T 1: ↓ I Q , r ea di ng , m at h T2 : ↓ IQ , w or ki ng m em or y, m at h = r ea ding B: T2 p ar en tal repo rt s: = T2 tea ch er repo rt s: ↓ e xe cu tiv e fu nc tio ning SP : T 2: 4 2% s pe ci al e du ca tio n, 1 0% repea ted gr ad e C : O ne -p er son ho us eho ld st at us , w ei gh t a t L Tx , b lo od tr an sf usi on s L Tx . Ee 201 4 C ro ss -sec tio nal Po st -LTx 6 – 1 7 y w n = 1 3; 4 6% b oy s Sib ling s: n = 6 8/ 13 B A 3/ 13 Al ag ille 1/1 3 A 1AT 1/1 3 P FI C W IS C -I V W IAT -I I WR AM L RC FT BR IEF D KE FS C PR CBCL C: = ↓ v is ual s can ning , in hib iti on , com pr ehe nsi on , 2 /3 s tor y m em or y su bt es ts (v er su s s ib ling s) ↓ m at h, v is ual m em or y ( LT x r ec ip ien ts and s ib ling s) B: ↓ a tt en tio n ( ver su s s ib ling s) ↓ an xi ou s, d epr es si ve behav io r, som at ic c om pl ai nt s, s oc ia l, t ho ug ht and a tt en tio n pr ob lem s, ru le -br eak ing , ag gr es si ve b eh av ior (v er sus norm s) Par en tal repo rt s: = N ot repo rt ed Ka lle r 201 3 C ro ss -sec tio nal Po st -LTx 6 – 1 8 y n = 6 4; 6 5% b oy s He al th y c ontr ol s: n = 6 4 >1 y r p os t-LTx 34 /6 4 B A 8/ 64 Ch ole st at ic d is eas es 10 /6 4 Gen et ic -m et abo lic dis or de rs 12/ 64 O th er s W IS C -I V C: ↓ 3 /4 i nd ex s ca le s ( ve rs us c on tr ol s) ↓ a ll ( ve rs us norm s) C : E tiolo gy o f liv er d is eas e: pr im ar y g en et ic -m et abo lic dis or de rs . L ow er he ig ht pe rc en til e a t L Tx , a h ig he r nu m be r o f d ay s s pe nt i n I C < 1 y p os t-LT x a nd o ld er a t L Tx .
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Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs Ha av is to 201 1 C ro ss -sec tio nal Po st -LTx 7 – 1 6 y n = 1 8; 3 9% b oy s He al th y c ontr ol s: n = 1 7 7/ 17 B A 3/ 17 A cut e he pa tit is e ci 2/ 17 H yper ox al ur ia 2/ 17 P ol yc ys tic k id ne ys 1/1 7 H epa to ce llu lar c ar cin om a 1/1 7 N eon at al he pa tit is 1/1 7 H ep at ob las to ma 1/1 7 O C T d efi ci en cy W IS C -III NE PS Y-II FTF C: = F SI Q , V IQ , a tt en tio n, e xe cu tiv e fu nc tio ns , m em or y and lear ning , lang ua ge fu nc tio ns ↓ P IQ , vi suo sp at ia l/vi suo co ns tr uc tiv e fu nc tion s, s oc ia l p er ce pt ion B: Par en tal repo rt s: ↓ m ot or sk ills , per cep tio n, m em or y, lear ning , s oc ial sk ill s, em ot io nal /behav io ral pr ob lem s = e xec ut iv e f un ct io ns , lang ua ge M : ↓ vi suo sp at ia l a nd vi suo co ns tr uc tiv e fu nc tion s SP : 3 4% s pec ial ed uc at io n, 6 % r epea ted gr ade C : L onger d is ea se d ur at io n. M : L onger d is ea se d ur at io n, ol de r a t LTx . So ren sen 201 1 C ro ss -sec tio nal Po st -LTx 5 – 7 y n = 1 44 ; 4 2% b oy s 84 /14 4 B A 14 /14 4 A LF 20 /14 4 O th er c ho les ta tic 14 /14 4 M et ab ol ic 12/ 14 4 O th er WPP SI -3 BB C S-R/ SR C W RAT -4 BR IEF Pe dsQ L ( sc ho ol fu nc tion ) C : ↓ F SI Q , V IQ , P IQ , r ea di ng , m at h = pr oc es sing s peed , g en er al lang uag e com po sit e, s cho ol re ad ine ss c om po sit e B: par en tal repo rt s: = e xec ut iv e f un ct io ni ng ↓ 1 /8 s ub sc al es (w or king m em or y) Tea ch er repo rt s: ↓ SP : 3 1% s pec ial ed uc at io n, 8 % r epea ted gr ade C /B : L Tx i n i nf an cy o r e ar ly ch ild hoo d G ilm our 201 0 Lo ng i-tud inal FU : 3 y Po st -LTx 6 – 1 8 y n = 8 23 ; 4 7% b oy s 30 7/ 82 3 B A 26 8/ 82 3 O th er c hole st at ic 115 /8 23 F ul m inan t l iv er fa ilu re 57 /8 23 C irrho sis 76 /8 23 O th er SA AP S SP : 3 4% s pec ial ed uc at io n, 2 0% repea ted gr ade SP : S pec ial e duc at io n pr e-LT x, u se o f c yc lo sp or in e or o the r non -c al ci ne uri n in hib ito r-ba sed imm un os uppr es si on , sy m pt om at ic C M V < 6 m on th s p os t-LTx .
Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs Ha av is to 201 1 C ro ss -sec tio nal Po st -LTx 7 – 1 6 y n = 1 8; 3 9% b oy s He al th y c ontr ol s: n = 1 7 7/ 17 B A 3/ 17 A cut e he pa tit is e ci 2/ 17 H yper ox al ur ia 2/ 17 P ol yc ys tic k id ne ys 1/1 7 H epa to ce llu lar c ar cin om a 1/1 7 N eon at al he pa tit is 1/1 7 H ep at ob las to ma 1/1 7 O C T d efi ci en cy W IS C -III NE PS Y-II FTF C: = F SI Q , V IQ , a tt en tio n, e xe cu tiv e fu nc tio ns , m em or y and lear ning , lang ua ge fu nc tio ns ↓ P IQ , vi suo sp at ia l/vi suo co ns tr uc tiv e fu nc tion s, s oc ia l p er ce pt ion B: Par en tal repo rt s: ↓ m ot or sk ills , per cep tio n, m em or y, lear ning , s oc ial sk ill s, em ot io nal /behav io ral pr ob lem s = e xec ut iv e f un ct io ns , lang ua ge M : ↓ vi suo sp at ia l a nd vi suo co ns tr uc tiv e fu nc tion s SP : 3 4% s pec ial ed uc at io n, 6 % r epea ted gr ade C : L onger d is ea se d ur at io n. M : L onger d is ea se d ur at io n, ol de r a t LTx . So ren sen 201 1 C ro ss -sec tio nal Po st -LTx 5 – 7 y n = 1 44 ; 4 2% b oy s 84 /14 4 B A 14 /14 4 A LF 20 /14 4 O th er c ho les ta tic 14 /14 4 M et ab ol ic 12/ 14 4 O th er WPP SI -3 BB C S-R/ SR C W RAT -4 BR IEF Pe dsQ L ( sc ho ol fu nc tion ) C : ↓ F SI Q , V IQ , P IQ , r ea di ng , m at h = pr oc es sing s peed , g en er al lang uag e com po sit e, s cho ol re ad ine ss c om po sit e B: par en tal repo rt s: = e xec ut iv e f un ct io ni ng ↓ 1 /8 s ub sc al es (w or king m em or y) Tea ch er repo rt s: ↓ SP : 3 1% s pec ial ed uc at io n, 8 % r epea ted gr ade C /B : L Tx i n i nf an cy o r e ar ly ch ild hoo d G ilm our 201 0 Lo ng i-tud inal FU : 3 y Po st -LTx 6 – 1 8 y n = 8 23 ; 4 7% b oy s 30 7/ 82 3 B A 26 8/ 82 3 O th er c hole st at ic 115 /8 23 F ul m inan t l iv er fa ilu re 57 /8 23 C irrho sis 76 /8 23 O th er SA AP S SP : 3 4% s pec ial ed uc at io n, 2 0% repea ted gr ade SP : S pec ial e duc at io n pr e-LT x, u se o f c yc lo sp or in e or o the r non -c al ci ne uri n in hib ito r-ba sed imm un os uppr es si on , sy m pt om at ic C M V < 6 m on th s p os t-LTx . Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs Ka lle r 201 0 C ro ss -sec tio nal Po st -LTx 5 - 1 2, 5 y n = 2 5; 5 2% b oy s 19 /2 5 B A 2/ 25 N eon at al he pa tit is 1/2 5 B ud d -C hi ar i s yndr om e 2/ 25 A cu te h ep at ic f ai lu re 1/2 5 W ils on ’s d is ea se K-AB C CB CL C: ↓ B: ↓ to tal behav io ral , in ter nal iz ing , ex ter nal iz ing pr ob lem s C : M ed ica l co m pl ic at io ns and behav io ral pr ob lem s. B: Yo un ge r a t o ns et o f di se ase . St eve ns on 201 0 Lo ng i-tud inal (ret ro sp .) FU : 2 y Pr and po st -LTx Pr e-LTx , 3, 1 2, a nd 2 4 m on th s po st -LTx n = 3 3; 4 5% b oy s C ontr ol s w ith B A: n = 3 1 M et abo lic d is or der s (L Tx < 4 2 m on th s o f a ge ); 9/ 33 H yper ox al ur ia 6/ 33 T yr osi ne mi a 3/ 33 C itr ul line mi a 3/ 33 O TC d efi ci en cy 2/ 33 A 1AT 2/ 33 GS D 1a 3/ 33 M et hy lm al on ic a ci de mi a 2/ 33 C PS d efi ci en cy 1/3 3 N eo na ta l he m oc hr om at osis 1/3 3 A SL d efi ci en cy 1/3 3 M ito chon dri al d is or de r w ith la ct ic a ci do sis BSI D W IS C WPP SI C : p re -LTx : ↓ (-1S D) 3 m on th s p os t-LT x: ↓↓ 1 y p os t-LT x: ↓ (b ac k a t p re -L Tx b as el in e) 2 y p os t-LT x: ↓, lo w -av er ag e ( no fu rt her in cr ea se ) M et ab ol ic d is or de rs < B A M : p re -LTx : ↓ (-2S D) 3 m on th s p os t-LT x: ↓ 1 y p os t-LT x: ↓ (ba ck a t pr e-LT x ba se lin e) 2 y p os t-LT x: ↓, lo w -av er ag e M et ab ol ic d is or de rs < B A SP : u rea c yc le pa tien ts : 3 /7 s pec ial ed uc at io n, 2 /7 a dd iti onal ed uc at io nal su ppo rt C /M : E tiolo gy o f liv er d is eas e: pr im ar y g en et ic -m et abo lic dis or de rs . G ilm our 20 09 C ro ss -sec tio nal Po st -LTx 0 – 1 8 y n = 3 0; 4 5% b oy s 21 /3 0 B A 3/ 30 A 1A T 4/ 30 N eon at al he pa tit is 2/ 30 Al ag ille BS ID -2 WPP SI -R W IAT BV M I VA BS C : = BA > o th er d ia gn os es B: = C : Dec rea sed h ei gh t pr e-LT x, el ev at ed s er um c al cin eu rin in hib ito r l ev el s po st -L Tx and hi gh es t m ea su red s er um am m on ia .
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Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs G rit ti 20 06 C ro ss -sec tio nal Po st -LTx 5 – 1 5 y n = 1 6; 5 0% b oy s C on tr ol s w ith s ta bl e ch ro ni c liv er d is eas e (w itho ut LT x) : n = 1 2 14 /1 6 B A 2/ 16 B yl er ’s d is ea se W IPP SI W IS C -R CB CL C : ↓ B: ↓ B: LT x i n c hi ld ho od . Ka lle r 20 05 C ro ss -sec tio nal Po st -LTx 5 - 1 3 y n = 4 4; 5 2% b oy s 31 /4 4 B A 4/ 44 Al ag ille 2/ 44 B yl er ’s d is ea se 2/ 44 N eon at al he pa tit is 1/4 4 H em oc hr om at osis 1/4 4 B ud d -C hi ar i s yndr om e 1/4 4 F ul m inan t h epa tic fa ilu re 1/4 4 W ils on ’s d is ea se 1/4 4 I nt ox ic ati on K-AB C ( 3 su bs ca les ) C: ↓ (> 15 m on th s o f a ge a t L Tx l ow er sc or es t ha n < 1 5 m on th s o f a ge a t L Tx ) C : A ge a t L Tx > 1 5 m on th s, ca da ve ric or ga n d on at ion , lo ng er d ur at io n o f illn es s and lo w er h ei gh t per cen til e at LTx . Ad ebä ck 20 03 C ro ss -sec tio nal Po st -LTx 4 – 1 7 y n = 2 1; 5 7% b oy s 8/ 21 B A 3/ 21 ALF 2/ 21 G SD 1a 2/ 21 T yr osi ne mi a 1/2 1 P FI C 1/2 1 A 1A Ta 1/2 1 H ep at ob las to ma , 1/2 1 C on ge ni ta l l iv er fi br os is 1/2 1 P rim ar y o xal ur ia 1/2 1 P FM LD W IS C -III WPP SI -R PH CS CS C : ↓ = (ve rs us p re -L Tx s co re s o r t im e a ft er LTx ) B: = SP : c hi ld re n > 7 y : 3 /1 3 i n l ow er g ra de o r w ith e xt ra tea ch ing re so ur ce s N ot repo rt ed
Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs Sch ul z 20 03 C ro ss -sec tio nal Po st -LTx 6 – 1 3 y n = 2 9; 4 8% b oy s 19 /29 BA 4/ 29 Al ag ille 2/ 29 P FI C 1/2 9 N eon at al he pa tit is 1/2 9 N eo na ta l he m oc hr om at osis 2/ 29 ALF K-AB C C : = ↓ s eq uen tial pr oc es sing s cal e SP : 5 5% 1 y ear beh ind in s ch oo l ed uc at io n C : O ld er and lo w er h ei gh t/ w ei gh t a t L Tx , a nd a ls o t o a l es ser d egr ee c adav er ic or ga n d on at ion (no t si gn ific an t) . Kr ul l 20 03 C ro ss -sec tio nal Po st -LTx 4 – 1 2 y n = 1 5; 2 7% b oy s C ontr ol s w ith C F: n = 1 5 13 /1 5 B A 1/1 5 A 1AT 1/1 5 P FI C W IS C -III WPP SI -R WJ -R DT VP -2 TO MAL C : ↓ V IQ , la ng ua ge a bi lit ie s, 2 /4 s ub te st s of m em or y ( ve rs us c on tr ol s) ↓ r ec ep tiv e l ang ua ge (-1S D) , t ot al , and ex pr es si ve lang ua ge (-2S D) (v er su s norm s) = m ea su re s o f a ca dem ic a ch ie vem en t M : = C : Y ou ng er a t L Tx , in cr ea sed nu mber o f d ay s in IC / pr olo ng ed h osp ita liz at io n < 1 y po st -L Tx , and e le va ted pr e-LT x b ili rub in le ve ls . G rit ti 20 01 C ro ss -sec tio nal Po st -LTx 4 – 1 1 y n = 1 8; 5 0% b oy s He al th y c ontr ol s: n = 1 8 12/ 18 B A 3/ 18 Cr ig le r N aj ja r 3/ 18 B yl er ’s d is ea se C AT WISC -R W IPP SI H um an Fi gu re Te st C: ↓ I Q ( ve rs us c on tr ol s) B: ↓ imm at ur ity o f eg o and dr iv es , f ear of d ea th , a nx ie ty o f l os s, a nd d ep re ss iv e fee ling s, m ild de fec t o f bod y im ag e and in ex pr es si ve h um an fi gu re s SP : n on e r eq uir ed s pec ial ed uc at io n, 2/ 12 1 y beh ind th ei r peer s B: Ea rly c hr on ic i lln es s i n com bi na tion w ith LT X.
2
Ta bl e 2 . C onti nu ed . Au th ors Year St udy d es ign Pa rt ic ip ants Ag e r an ge y ; n; % bo ys ; c on tr ols Liv er d ise ase Ass ess m en t C ogn iti ve , b eha vi or al and /or m ot or ou tc ome s c om par ed to n or m s or con tr ol gr oup s Ri sk f ac to rs Van M ou rik 2000 Lo ng i-tud inal FU : 4 y Pr e- a nd po st -LTx < 5 y n = 2 5; 2 8% b oy s 19 /2 5 B A 2/ 25 P er ina tal ly a cq uir ed fu lm inan t h epa tit is 1/2 5 F ul mi na nt non -A , non -B he pa tit is 1/2 5 N eon at al he pa tit is 1/2 5 N eo na ta l he m oc hr om at osis 1/2 5 A 1AT G M DS C : P re -LTx : = 4 y f ol lo w -u p: = (6 i nf an ts : ↓ la ng ua ge sk ills at 1 y follo w -up , = a t 4 y f ol lo w -u p) B: 1 y f ol lo w -u p: 5 i nf an ts ↓ s oc ia l sk ills 4 y : a lm os t p re -L Tx l ev el s M : = M : L ow n ut rit ion al s ta tus and d ec re as ed m us cl e b ul k pe ri-LTx . hi gh s cor es /si gn ific an tly h ig he r t ha n norm s or c on tr ol g ro up s; = a ve ra ge s cor es /no si gn ific an t d iff er enc e w ith norm s or c on tr ol g ro up s; ↓ /= l ow -a ve ra ge s co re s; ↓ l ow s co res / si gn ifi ca nt ly lo w er th an n or m s o r c on tr ol g ro up s. F U, fo llo w -u p; T 1, T im e p oi nt 1; T 2, T im e p oi nt 2 ; y , y ea r. B, b eh avi or al o ut come s; C , c og ni tiv e o ut come s; M, m ot or o ut come s; S P, sch oo l pe rf or m an ce . A 1A T, al ph a -1 -a nt itr yp si n de fic ie nc y; A LF , a cu te li ve r f ai lu re ; B A , b ili ar y a tr es ia ; F SI Q , f ul l s ca le IQ ; G SD , g ly co ge n st or ag e di se as e; LT x, li ve r t ra ns pl an ta tio n; N L, na tiv e liv er ; P FI C , pr ogr es si ve fam ili al in tr ah epa tic c ho le st as is ; P FM LD , pr ogr es si ve fam ili al m et abo lic li ver d is or der ec i; P IQ , per fo rm an ce IQ ; P V T, po rt al v ein th ro mbo si s; V IQ , v er bal IQ . As se ss m en t t oo ls : B RI EF , B eh av io r R at in g In ve nt or y of Ex ec ut iv e Fu nc tio n; BB C S-R/ SR C , B ra ck en Ba si c C on ce pt Sc al e Re vi se d , S ch oo l R ea di ne ss C om po si te ; B SI D , B ay le y Sc al es of In fa nt D ev elo pm en t; B VM I, B eer y V is ua l M ot or In teg ra tio n T es t; C AT , C hil dr en Apper cep tio n T es t; C BC L, C hil d B ehav io r C hec kli st ; C D I, C hil dr en ’s D epr es si on In ven to ry; C PR , C on ner ’s Par en t R at ing S cal e; D KE FS , De lis K ap lan E xec ut iv e Fun ct io ni ng S ys tem ; D TV P, De ve lo pm en tal T es t o f V is ual P er cep tio n; F TF , Fi ve to Fi ft een Q ue st io nna ire ; G M D S, G rif fit hs M en tal Ab ili ty S cale ; K -A BC , K au fm an A ss es sm en t B at ter y f or C hil dr en ; M -A BC , M ov em en t A ss es sm en t B at ter y f or C hil dr en ; P H C SC S, T he P ier s-H ar ris S el fc on cep t S cale ; RC FT , R ey C om ple x Fi gu re T es t and R ec ogn iti on T rial ; S A AP S, S ch oo l A tt end an ce and A ca dem ic P er fo rm an ce S ur ve y; T O M AL , T es t o f M em or y and L ear ning ; V AB S, V in el and A dap tiv e Behav io r S cal e; W IA T, W ec hs le r I nd iv id ua l A ch ie ve m en t T es t; W IS C , W ec hs le r I nt el lig en ce Sc al e f or C hi ld re n; W J-R, W oo dco ck ,J oh ns on T es ts o f A ch ie ve m en t R ev is ed ; W PP SI , W ec hs le r p res ch oo l an d p rim ar y s ca le o f i nt el lig en ce ; W RA M L, W id e R an ge A ss es sm en t o f M em or y a nd L ea rn in g; W RA T, W id e R an ge A ch ie ve m en t T es t.
Discussion
The aim of this systematic review, executed in accordance to the PRISMA guidelines, was to provide an overview of the current literature on the neurodevelopmental outcomes in children with liver diseases who still had their native livers and/or after LTx and to identify possible risk factors for impaired outcomes. The treatment possibilities of children with liver diseases have improved significantly over the last decades and survival rates are increasing, making it a chronic rather than a fatal disease. It is therefore essential to gain insight into the long-term sequel of liver diseases in childhood.
All studies reported deficits in one or more areas, be it in the cognitive, motor, or behavioral domains. The majority of the studies reported cognitive deficits in children with liver diseases with their native livers (4/6 studies; 67%) and in children after LTx (14/17 studies; 82%). In children with their native livers, as well as after LTx, low IQ scores were the most predominant outcome. All studies in children surviving with their native livers, and most studies including children after LTx, showed low-average and significantly abnormal scores on subscales of cognitive and behavioral measures. Also, a remarkable percentage of children after LTx received special education or had already repeated one or more classes (up to 42%). Of nine studies describing motor outcomes, seven described impairments in one or more subtests of motor development (82%). The two other studies described average scores on motor development, with slightly higher scores in children with native livers compared
to children after LTx.24 Remarkably, there are more studies on neurodevelopmental
outcomes in children with LTx compared to children with liver diseases who still had their native livers. There is little to no data on behavioral outcomes nor on school performance of children with liver diseases who still had their native liver.
Factors that appeared to be associated with neurodevelopmental outcomes were variable to some extent. The impaired neurodevelopmental outcomes in children with liver diseases without LTx or before LTx suggest that a liver disease itself influences neurodevelopment, which might or might not be aggravated by surgical therapy and its sequel. Gilmour et al. showed that children at highest risk for special education post-LTx were those who already received special education pre-LTx or those who were too young and not yet in school at time of LTx. This suggests that neurodevelopmental deficits were, to some extent, already present before LTx. Etiology of liver diseases plays an important role in neurodevelopmental impairment. Cognitive outcomes
were more impaired in children with metabolic disorders than in children with BA or other cholestatic diseases. We have to bear in mind that in some liver diseases, for example, the metabolic induced liver diseases, impaired neurodevelopment might be explained by brain damage due to the underlying disease. Poor adherence to
therapy could also influence neurodevelopmental outcome in certain liver diseases.21
In some children with liver failure, either acute or chronic, the neurodevelopmental
deficits recovered following adequate treatment and LTx.11 This is in line with previous
studies that reported improvement in neurodevelopment after LTx.3,32 Results on
whether motor outcomes improved over time after LTx were inconsistent; two studies
showed improvement after LTx and one study did not.9,28,29
Other studies showed that LTx itself is an important contributory factor to
neurodevelopmental impairment.19,24,27 Nevertheless, Stevenson and colleagues
showed that negative effects of LTx on neurodevelopment can be reversible within
one year after LTx.9 The factor most associated with neurodevelopmental outcome
was growth failure at the time of LTx. Growth failure might be caused by malnutrition which, in early childhood, is associated with dendritic spine abnormalities, short apical dendrites, fewer spines and altered neurotransmitter function and
responsiveness.33 Recently Lurz et al. showed that children with end-stage liver
disease had a significantly lower psoas muscle surface area when compared to age-matched healthy controls. This suggests an impaired nutritional status in children
with end stage liver disease.34 Improved nutritional status peri-LTx was associated
with increased muscle bulk and subsequent improvement in motor scores.29 Based
on current data, nutrition seems to be the only risk factor amenable to a short-term potential intervention to improve neurodevelopmental outcome.
The effect of general anesthesia in early childhood on neurodevelopment is still unclear. Numerous cohort studies found conflicting evidence for an association
between exposure to general anesthesia and neurodevelopmental outcomes.35–37
To the best of our knowledge the association between general anesthesia and neurodevelopmental outcome in children with liver diseases has not been investigated yet. Furthermore, exposure to general anesthesia was not found as a risk factor for impaired neurodevelopmental outcome in the included articles of this review.
In one of the multi-center cohort studies, Gilmour et al. showed that both treatment with calcineurin inhibitors and with non-calcineurin inhibitors post-LTx was
associated with impaired cognitive outcomes and special education.21,31 Calcineurin
inhibitors and non-calcineurin inhibitors, as well as exposure to steroids at young age,
are known for its neurotoxicity.38–40 More research is needed to explore the potential
risk of immunosuppressive regimens post-LTX for neurodevelopmental impairments. Other factors associated with impaired neurodevelopmental outcomes concerning LTx were younger age at LTx and longer duration of hospitalization. Studies on children with BA showed that younger age at LTx is associated with better cognitive
development. 8,10,15,18,23,26 This might be due to a better nutritional status and growth,
shorter exposure to the liver disease and earlier normalization of toxic liver values after transplantation at a younger age, possibly also at an age period in which the brain has higher plasticity to adapt. Other studies showed that children who underwent transplantation in the first six months after birth have more impaired
neurodevelopmental outcomes in comparison to controls or the norm population.3,17,41
The children who underwent LTx before the age of six months are predominantly children with BA with insufficient therapeutic effects of Hepato-portoenterostomy (Kasai procedure) necessitating LTx at this young age. It is tempting to speculate that the worse outcomes in these children are due to the underlying liver disease and not to the surgical intervention per se.
Our conclusion is that this review shows that children with liver diseases are prone to neurodevelopmental impairments. The studies included in this review show that children with liver diseases are at risk of deficits in all areas of neurodevelopment, i.e. cognition, behavior, and motor development. Even though the mean scores predominantly fall within the average range, most scores are lower than scores in the norm population or control groups. Moreover, it is obvious that a remarkably larger number of children have abnormal scores on neurodevelopment when compared to control groups or norm population. The limited number of studies in this field suggests that this population is struggling in growing up to productive, independent young adults. It might be that both adequate medical and/or surgical treatment of liver diseases and more ‘aggressive’ nutritional management contribute to better neurodevelopmental outcomes. Both are of great practical importance in the day-to-day lives of children and their families who experience many problems because of neurodevelopmental impairments. Furthermore, the findings
emphasize that special attention to neurodevelopmental sequel in children with liver diseases needs to be given during follow-up and possible intervention programs with neuropsychologists, physiotherapists, and rehabilitation consultants are warranted. Unfortunately, it is difficult to investigate neurodevelopmental outcomes in homogenous groups of adequate sample sizes, as pediatric liver diseases are (relatively) rare. In consequence, the knowledge gap is worrying, especially when one takes into consideration that survival rates are improving and that as a consequence the number of at-risk patients is increasing. We believe that this patient group might benefit from intervention programs in analogy to preterm infants. Previous research in preterm born infants has shown the benefits of an early intervention
program to improve neurodevelopmental outcomes.42,43 However, liver disease often
is a more chronic condition. Research is needed to explore the potential benefits of neurodevelopmental intervention programs to improve long-term outcomes in children with liver disease. This systematic review forms the basis for a prospective study that should provide more insight into the steps that have to be taken to improve neurodevelopmental outcome in children with liver diseases.
Limitations
Even though there was a reasonable overlap in the findings of the studies described in this review, there were notable differences too. These differences are probably due to the heterogeneity of the studies and in the types of liver diseases. Sample sizes in the majority of the studies were small. Due to the nature of retrospective cohort studies, confounders may have biased results on risk factors of deficits. As presented in Table 1 and 2, studies were highly divergent with respect to:
1. Target population, in sense of age of patients (0-18 years) and etiology of liver diseases (over 30 different etiologies).
2. Measurement of outcomes, that is, 28 different test batteries and questionnaires were used to measure cognition, behavior and/or motor outcomes.
Given these differences in applied design and methods, the outcome per each outcome (cognition, behavior and motor outcome) from one study may not be the same as in the other included studies. This hinders comparability of results across studies and hence a meaningful statistical analysis of combined results becomes infeasible. Well-designed randomized controlled trials are essential for more reliable results.
Future implications
We conclude that children with liver diseases are at increased risk of deficits in one or more areas of neurodevelopment be it in the cognitive, motor, or behavioral domains. In our opinion, adequate long-term follow-up studies to investigate the developmental trajectories of children with liver diseases are urgently required. Future research is necessary to determine early predictors and risk factors, and to explore the possibilities with regard to interventions that could eventually improve the long-term neurodevelopmental outcomes to support these vulnerable patients in growing up to productive, independent young adults.
References
1. Anderson V. Developmental neuropsychology: A clinical approach. Psychol Press.
2001;555.
2. Xiong T, Gonzalez F, Mu DZ. An overview of risk factors for poor neurodevelopmental
outcome associated with prematurity. World J Pediatr. 2012;8:293–300.
3. Wayman KI, Cox KL, Esquivel CO. Neurodevelopmental outcome of young children
with extrahepatic biliary atresia 1 year after liver transplantation. J Pediatr. 1997;131:894–898.
4. Stewart SM, Campbell RA, McCallon D, et al. Cognitive patterns in school-age
children with end-stage liver disease. Journal of Developmental and Behavioral
Pediatrics. 1992;13:331–338.
5. DiMaggio C, Sun LS, Ing C, et al. Pediatric Anesthesia and Neurodevelopmental
Impairments. J Neurosurg Anesthesiol. 2012;24:376–381.
6. Sorensen LG, Neighbors K, Zhang S, et al. Neuropsychological Functioning and
Health-Related Quality of Life: Pediatric Acute Liver Failure Study Group Results. J
Pediatr Gastroenterol Nutr. 2015;60:75–83.
7. Kaller T, Boeck A, Sander K, et al. Cognitive abilities, behaviour and quality of life in
children after liver transplantation. Pediatr Transplant. 2010;14:496–503.
8. Schulz K-H, Wein C, Boeck A, et al. Cognitive performance of children who have
undergone liver transplantation. Transplantation. 2003;75:1236–40.
9. Stevenson T, Millan MT, Wayman K, et al. Long-term outcome following pediatric
liver transplantation for metabolic disorders. Pediatr Transplant. 2010;14:268–275.
10. Caudle SE, Katzenstein JM, Karpen SJ, et al. Language and Motor Skills Are Impaired
in Infants with Biliary Atresia Before Transplantation. J Pediatr. 2010;156:936-940.
11. Srivastava A, Yadav SK, Borkar V V, et al. Serial evaluation of children with ALF
with advanced MRI, serum proinflammatory cytokines, thiamine, and cognition assessment. J Pediatr Gastroenterol Nutr. 2012;55:580–586.
12. Abu Faddan NH, Shehata GA, Abd Elhafeez HA, et al. Cognitive function and
endogenous cytokine levels in children with chronic hepatitis C. J Viral Hepat. 2015;22:665–670.
13. Rodrigue JR, Balistreri W, Haber B, et al. Impact of hepatitis C virus infection on
children and their caregivers: quality of life, cognitive, and emotional outcomes.
J Pediatr Gastroenterol Nutr. 2009;48:341–347.
14. Soogoor M, Lynn HS, Donfield SM, et al. Hepatitis C virus infection and neurocognitive
function. Neurology. 2006;67:1482–1485.
15. Caudle SE, Katzenstein JM, Karpen S, et al. Developmental Assessment of Infants
16. Gritti A, Di Sarno AM, Comito M, et al. Psychological impact of liver transplantation
on children’s inner worlds. Pediatr Transplant. 2001;5:37–43.
17. Krull K, Fuchs C, Yurk H, et al. Neurocognitive outcome in pediatric liver transplant
recipients. Pediatr Transplant. 2003;7:111–118.
18. Kaller T, Langguth N, Petermann F, et al. Cognitive performance in pediatric liver
transplant recipients. Am J Transplant. 2013;13:2956–2965.
19. Sorensen LG, Neighbors K, Martz K, et al. Cognitive and Academic Outcomes after
Pediatric Liver Transplantation: Functional Outcomes Group (FOG) Results. Am J
Transplant. 2011;11:303–311.
20. Sorensen LG, Neighbors K, Martz K, et al. Longitudinal Study of Cognitive and
Academic Outcomes after Pediatric Liver Transplantation. J Pediatr. 2014;165:65-72.
21. Gilmour S, Adkins R, Liddell GA, et al. Assessment of psychoeducational outcomes
after pediatric liver transplant. Am J Transpl. 2009;9:294–300.
22. Adebäck P, Nemeth A, Fischler B. Cognitive and emotional outcome after pediatric
liver transplantation. Pediatr Transplant. 2003;7:385–9.
23. Haavisto A, Korkman M, Törmänen J, et al. Visuospatial impairment in children and
adolescents after liver transplantation. Pediatr Transplant. 2011;15:184–192.
24. Gold A, Rogers A, Cruchley E, et al. Assessment of School Readiness in Chronic
Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation. Can J Gastroenterol Hepatol. 2017;9873945.
25. Ee LC, Lloyd O, Beale K, et al. Academic potential and cognitive functioning of
long-term survivors after childhood liver transplantation. Pediatr Transplant. 2014;18:272– 279.
26. Kaller T, Schulz K-H, Sander K, et al. Cognitive Abilities in Children after Liver
Transplantation. Transplantation. 2005;79:1252–1256.
27. Gritti A, Sicca F, Di Sarno AM, et al. Emotional and behavioral problems after
pediatric liver transplantation: A quantitative assessment. Pediatr Transplant. 2006;10:205–209.
28. Almaas R, Jensen U, Loennecken MC, et al. Impaired motor competence in children
with transplanted liver. J Pediatr Gastroenterol Nutr. 2015;60:723–728.
29. van Mourik ID, Beath S V, Brook GA, et al. Long-term nutritional and
neurodevelopmental outcome of liver transplantation in infants aged less than 12 months. J Pediatr Gastroenterol Nutr. 2000;30:269–275.
30. Sorensen LG, Neighbors K, Martz K, et al. Longitudinal Study of Cognitive and
Academic Outcomes after Pediatric Liver Transplantation. J Pediatr. 2014;
165:65-72.e2.
31. Gilmour SM, Sorensen LG, Anand R, et al. School outcomes in children registered
in the Studies for Pediatric Liver Transplant (SPLIT) consortium. Liver Transplant. 2010;16:1041–1048.
32. Hobbs SA, Sexson SB. Cognitive development and learning in the pediatric organ
transplant recipient. J Learn Disabil. 1993;26:104–113.
33. Holden KR. Malnutrition and brain development: a review. J Pediatr. 1969;74:667–679. 34. Lurz E, Patel H, Frimpong RG, et al. Sarcopenia in Children With End-Stage Liver
Disease. J Pediatr Gastroenterol Nutr. 2018;66:222–226.
35. Andropoulos DB, Greene MF. Anesthesia and developing brains - Implications of
the FDA warning. Obstetrical and Gynecological Survey. 2017;72:468–469.
36. Zhang H, Du L, Du Z, et al. Association between childhood exposure to single general
anesthesia and neurodevelopment: a systematic review and meta-analysis of cohort study. J Anesth. 2015;29:749–757.
37. Davidson AJ, Disma N, De Graaff JC, et al. Neurodevelopmental outcome at 2
years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomised controlled trial. Lancet. 2016;387:239–250.
38. Patchell RA. Neurologcal Complications of Organ Transplantation. 1994;688–703. 39. Bechstein WO. Neurotoxicity of calcineurin inhibitors: Impact and clinical
management. Transpl Int. 2000;13:313–326.
40. Shinwell ES, Eventov-Friedman S. Impact of perinatal corticosteroids on neuromotor
development and outcome: Review of the literature and new meta-analysis. Semin
Fetal Neonatal Med. 2009;14:164–170.
41. Alonso EM, Sorensen LG. Cognitive development following pediatric solid organ
transplantation. Curr Opin Organ Transplant. 2009;14:522–525.
42. Nordhov SM, Rønning JA, Dahl LB, et al. Early intervention improves cognitive
outcomes for preterm infants: randomized controlled trial. Pediatrics. 2010;126:e1088-94.
43. Van Hus J, Jeukens-Visser M, Koldewijn K, et al. Early intervention leads to
long-term developmental improvements in very prelong-term infants, especially infants with bronchopulmonary dysplasia. Acta Paediatr. 2016;105:773–781.
