Fatty Liver Disease in - ePrints Soton · 2019-12-16 · Non‐alcoholic fatty liver disease (NAFLD) is a multifactorial disorder closely associated with the metabolic syndrome and

NonalcoholicFattyLiverDiseaseinchildren

Mann,JakeP1,MD;[email protected].

Valenti,Luca2,MD;[email protected].

Scorletti,Eleonora3,MD;[email protected]

Byrne,ChristopherD3,4,MD;[email protected]

Nobili,Valerio5,6,MD;[email protected]

1. Departmentofpaediatrics,UniversityofCambridge,Cambridge,UK;

2. FondazioneIRCCSCa'GrandaOspedalePoliclinicoMilano,Departmentof

PathophysiologyandTransplantation,UniversitàdegliStudidiMilano,

Milan,italy.

3. HumanDevelopmentandHealthAcademicUnit,FacultyofMedicine,

UniversityofSouthampton,Southampton,UnitedKingdom

4. NIHRSouthamptonBiomedicalResearchCentre,UniversityHospital

SouthamptonNHSFoundationTrustandUniversityofSouthampton,

Southampton,UnitedKingdom

5. HepatometabolicUnit–BambinoGesùChildren’sHospital–Rome,Italy

6. DepartmentofPediatric–University“LaSapienza”‐Rome,Italy

Correspondingauthor:

Prof.ValerioNobili,MD

DepartmentofPediatric–University“LaSapienza”,andHepatometabolic

DiseaseUnit,BambinoGesùChildren’sHospitalIRCCS(InstitutodiRicoveroe

CuraaCarattereScientifico),P.leS.Onofrio,4–00165Rome,Italy.Tel.:+3906

68592192.

ShortTitle:PediatricNAFLD

Totalwordcount=5876

Numberoffiguresandtables:4tablesplus1Figure

References:134

ListofAbbreviations:NAFLD=Non‐alcoholicfattyliverdisease;NAFL=Non

alcoholicfattyliver;NASH=Non‐alcoholicsteatohepatitis;

Conflictofintereststatement:Allauthorsdeclarethatthereisnoconflictof

interestthatcouldbeperceivedasaffectingtheimpartialityofthereported

research.

Financialsupportstatement:Noexternalfundingsupportedtheresearch

describedinthismanuscript.Thisresearchdidnotreceiveanyspecificgrant

fromanyfundingagencyinthepublic,commercialornot‐for‐profitsector.

Authorscontribution:Allauthorsequallyparticipatedtothemanuscript,

approvedthefinalversionassubmitted,andagreetobeaccountableforall

aspectsofthework.

Abstract

Non‐alcoholic steatohepatitis (NASH),aprogressive formofnon‐alcoholic fatty

liverdisease (NAFLD), isoneof themost commonhepaticdiseases inchildren

who present with particular risk factors, including obesity, sedentary lifestyle

and/orapredisposinggeneticbackground.TheprevalenceofNAFLDinchildren

worldwideisaworryingphenomenonbecausethisdiseaseiscloselyassociated

with the development of both cirrhosis and cardiometabolic syndrome in

adulthood. To date the etiopathogenesis of primary NAFLD in children is still

unknown. Understanding the pathogenetic mechanisms provide the basis to

characterize early predictors of the disease, noninvasive diagnostic tools and

designnovelspecifictreatmentsandpossiblemanagementstrategies.Despitea

fewclinicaltrialsontheuseofantioxidantscombinedwithlifestyleintervention

for NAFLD, no treatment exist for children with NAFLD. In this Review, we

provideanoverviewofcurrentconcepts inepidemiology,histological features,

etiopathogenesis,diagnosisandtreatmentofNAFLDinpediatricpopulation.

Keyword:NAFLD,obesity,children,NASH

Introduction

Non‐alcoholic fatty liver disease (NAFLD) is a multifactorial disorder closely

associated with the metabolic syndrome and is the most common cause of

abnormalliverfunctiontests(LFT)inchildren.NAFLDissettobecomethetop

cause for liver transplantation in adults and, whilst it is rare for children to

develop end‐stage liver disease from NAFLD, they may become cirrhotic as

adults.UnderstandingandmanagingNAFLDinchildrenmayrepresentamethod

to intervene early and alter the disease process. Furthermore, children with

steatosisrequirecarefulassessmentasitmaybesecondarytootherconditions

(e.g.Wilsondisease).Forthesereasons,paediatricNAFLDisofhighimportance

totheallgastroenterologists,hepatologists,andpaediatricians.

NAFLDrefers toa spectrumofdisease, ranging fromhepatic steatosis (‘simple

steatosis’, or non‐alcoholic fatty liver (NAFL)), non‐alcoholic steatohepatitis

(NASH)withorwithoutfibrosis,andend‐stageliverdisease.Diagnosisrequires

radiological(orhistological)demonstrationofsteatosis,exclusionofsecondary

causes, andno significantalcohol intake.Childrenpresent in threemainways:

incidentalabnormalLFT/imaging,screeninginobesity,andduringinvestigation

ofabdominalpain,thecauseofwhichisnotclear.

In thisreviewweaimtoprovideanoverviewofpaediatricNAFLDanddiscuss

managementinthecontextofrecentguidance.

Epidemiology

Paralleling thedramatic rise inpediatricobesityworldwide,nonalcoholic fatty

liverdisease(NAFLD)hasbecomealeadingcauseofchronicliverdiseaseduring

thedevelopmental age, and themaindeterminantonpediatric liverdisease in

Westerncountries1. Several studieshavedemonstratedaprevalenceof3–10%

in general pediatric populations,which increases up to 60–70% in individuals

with metabolic comorbidities2. However, NAFLD prevalence varies widely

dependingongeographicalareaanddiagnosticmethodsused.

Initial population based studies, which estimated the prevalence of paediatric

NAFLD by determining aminotransferases or by ultrasonography in several

countries, have indicated a prevalence range of 3–7%1. In an autoptic study,

conducted in unselected children deceased for accidents in California, the

prevalenceofhistologicalNAFLDrangedfrom0.7%in2–4yearsold,to17.3%in

15–19yearsoldsubjects,butincreasedto38%inobesechildren3.Incohortsof

children of various nationalities selected for overweight or obesity, the

prevalenceofelevatedALTwashigherandrangingfrom8to42%,whereasthe

prevalenceofbrightliverrangedfrom1.7to77%4.Arecentattempttoexamine

NAFLDprevalencebasedonameta‐analysisofstudiesconductedin76different

populations led to an estimate of 7.6% (95% CI 5.5‐10.3%) in the general

population, and 34.2% (27.8‐41.2%) in obesity clinics5. However, therewas a

huge heterogeneity (I2=98%), which was partly accounted for by the sex

distribution, difference in BMI and ethnicity, with NAFLD prevalence being

higher in males, individuals with more severe adiposity, and in Asians.

Importantly, use of liver enzymes instead of imaging to diagnoseNAFLD led a

significantunderestimationofdiseaseprevalence5.

Indeed,obesityandmetabolicsyndromefeaturesarethemajorrisk factors for

paediatric NAFLD. The prevalence of this condition is higher in overweight

(gender and age specific body mass index BMI >85th percentile) or obese

(>95th) children as comparedwith normal weight pairs. However, due to the

closestlinktoinsulinresistance,centraladiposity,thatisaccumulationoffatin

visceral organs, plays a specific contribution in determining disease risk6,7.

Indeed,waistcircumference,aneasilyavailable indexofvisceral fat, correlates

withNAFLDindependentlyofBMI1,8.

Nutritional factors such as excessive intake of calories, processed food and a

sedentarylifestyleplayakeyroleinthepredispositiontoliverfataccumulation,

NAFLD and progressive liver disease9,10. Fructose intake has emerged as an

important determinant of NAFLD risk, independently of total caloric intake,

probablyduetotheabilitytostimulatedenovolipogenesis11,12.Thishasrecently

beendemonstratedtotranslateintoincreasedriskofNASH13.Thequalityoffat,

and specifically a reduced omega‐3/omega‐6 ratio, has also been reported to

predisposetoNAFLDinchildrenathigherrisk14.Ontheotherhand,highlevels

ofphysicalactivityareassociatedwithprotectionfromNAFLD8.

Inherited factors account for a large proportion of the inter‐ethnic and inter‐

individualvariability inthepredispositiontoNAFLD.Geneticstudieshavenow

identifiedthespecificcommonvariantsthatinfluencehepaticfatmetabolismas

important determinants of NAFLD in children and adults15–17. Also in the

developmental age, NAFLD is more prevalent in individuals of Hispanic and

AsianethnicityascomparedtoEuropeans,whereasthoseofAfricanancestryare

relativelyprotected5,18.Themostvalidatedgeneticrisk factorsarethePNPLA3

I148MandTM6SF2E167Kmutations,whichinfluencelipiddropletremodeling

and the secretion of lipids from hepatocytes19–21, GCKR P446L regulating

lipogenesis22, and genetic variation in the MBOAT7 that affects acyl chain

remodelingof phosphatidyl inositol17. Evaluationof these genetic risk variants

increasestheabilitytostratifytheriskofNAFLD23.Recentstudiesalsosuggesta

linkbetweenNAFLDandepigeneticmodifications,stablechangesinexpression

of DNA related to chemical modifications of DNA and chromatin structure,

caused by exposure to environmental factors24. In fact, accumulating evidence

suggests that an adverse intrauterine environment as detected by low birth

weightisassociatedwithincreasedriskofpediatricandadultNAFLD23,25

Histology

Fromahistopathologicalpointofview,NAFLDencompassesadiseasespectrum

ranging from “simple steatosis” (nonalcoholic fatty liver), to nonalcoholic

steatohepatitis(NASH),whichischaracterizedbythepresenceofhepatocellular

damage under the form of ballooning and mixed lobular inflammation, is

associatedwithactivationofpericellular‐perisinusoidalfibrogenesisandevolve

in a variable proportion of cases to fibrosis, cirrhosis, and hepatocellular

carcinoma26. Other common features include Mallory‐Denk’s bodies,

megamitochondria,acidophilbodies,andironaccumulation27.

NASH is associated with faster progression of liver fibrosis as compared to

simple steatosis28. Importantly, fibrosis stage is the main determinant of the

prognosis of patients with NAFLD, both concerning liver‐related and overall

mortality29–32.

Pediatric NAFLD displays some peculiar histological features compared to the

adult form, and, unlike the adult disease, are rarely influenced by some

secondarylifestylefactors(e.g.,alcohol,drugs),whereasothermayhaveamore

prominentrole(e.g. fructose intake). Indeed, twodifferent typesofhistological

damagehavebeendescribedinchildrenwithNAFLD33.Thesehavebeencalled

“Type1”and“Type2”NAFLD.Type1NAFLDreferstothehistologicalfeatures

classically associated with NASH in obese adults. These are represented by

steatosis,thatisaccumulationofneutrallipidswithinintracellularlipiddroplets,

whichisgenerallymoresevereinthecentrilobulararea.Thisisaccompaniedby

hepatocellular damage under the form of ballooning, lobular inflammation

and/orperisinusoidal fibrosis. In contrast, Type2NAFLDhas beendescribed

morefrequentlyduringthedevelopmentalage,andischaracterizedbysteatosis

with portal inflammation and/or periportal fibrosis. This form is more

commonly observed inmales and in childrenofHispanic orAsianethnicity as

comparedtoEuropeans33.However, in themajorityofseries itwas foundthat,

although Type 2 features are more frequent, most pediatric patients display

overlappingfeaturesofType1andType2NAFLD,whichcanbeconsideredthe

twoextremesofapathologicalspectrum34–36.Importantly,portalinflammation,

whichistypicalofType2NAFLD,hasbeenassociatedwithmoreseverefibrosis

stage37.

Inarecentseries,of440CaucasianchildrenwithhistologicalNAFLD,12%had

Type1,22%type2Type2,and66%overlappingfeatures38.Remarkably,those

with type 2 had a more severe metabolic phenotype, with higher central

adiposityanddyslipidemia.Furthermore,thepresenceofportalinflammation,a

feature of Type 2 NAFLD, was independently associated with waist

circumferenceandclinicallysignificantfibrosis,suggestingthatthishistological

featureisinvolvedinmediatingfasterprogressionofthedisease.

PathogenesisofNAFLDinchildren

Thepathogenesisofnon‐alcoholicfattyliverdisease(NAFLD)inadultshasbeen

well‐defined39–42. In contrast, the pathogenesis of NAFLD in children has not

beentheobjectofcomparableattentionand, thus, itscontributingfactorshave

yettobemappedcomprehensivelyandfullyunderstood.Below,wedescribethe

key pre‐natal and post‐natal factors that have been shown to affect the

pathogenesisofNAFLDinchildren.

Pre‐natalfactors

Recent evidence has shown that there are some pre‐natal factors that are

responsibleforthepathogenesisofpaediatricNAFLDsuchasmaternalobesity,

metabolic syndrome during pregnancy, gestational diabetes and low birth

weight43–46.This is supportedbya seriesofwell‐conducted invitro and invivo

mechanisticstudies.Itisamultifactorialprocessthatresultsfromacombination

ofbiochemical factors(foetal insulin, lipidprofile)andepigeneticmodification,

which influences hepatic de novo lipogenesis, mitochondrial function, and

oxidativestressinhepatocytes,macrophages,andadipocytes47–53.Itisgenerally

agreed that a ‘second hit’ is required to initiate development of NAFLD as an

adolescentoradult,forwhichmostisapositiveenergybalanceintheformofa

high‐fat/‐carbohydrate (‘Western’) diet46,51,52,54. Recent human studies showed

that there is an associationbetweenmaternal pre‐pregnancybodymass index

(BMI) and infant ectopic fat deposition in the liver and in the intra‐abdominal

cavity45 (Table 1). Magnetic resonance imaging has been used to measure

adiposity and hepatic liver fat in the new‐born infant of obese mothers and

womenwith gestational diabetes44,45 and in one of these studies a correlation

wasshownbetweengestationalBMIandoffspringhepaticlipidaccumulation45.

Though it is unclearwhether these same infants go on to developprogressive

NAFLD. A possible explanation for the ectopic hepatic fat deposition in these

newborn infants may be that immature foetal adipocytes are not sufficiently

developed to accommodate and store lipids crossing the placenta in excess,

throughout pregnancy. Consequently, in the presence of maternal obesity or

gestational diabetes mellitus, two states where non‐esterified fatty acid

concentrations might be expected to be increased, excess transference of

maternallipidwillresultinaccumulationoffetalectopicfatasthefoetusisnot

able to expand adipose depots to buffer the increased transplacental lipid

delivery55.Thepresenceandpersistenceofliverfatafterbirthhasalsobeshown

byusinamousemodeldevelopedtoinvestigatedevelopmentalprogrammingof

offspringNAFLD56.Inthisstudy,weshowedthatincreaseddietarymaternalfat

intakeinthemotherfrombeforeconception,primeddevelopmentofincreased

liverfatintheoffspringmiceinadulthood,eveniftheoffspringmousehadonly

evereatenanormalchow(carbohydrate‐rich, low fat)diet fromweaninguntil

adulthood. Furthermore, in adult mice that had been exposed in utero to

increased dietary maternal fat intake in the mother from before conception,

coupled with only consuming the same high fat diet from weaning until

adulthood,thesemicedevelopedafloridformofNASH,thatwasaconsiderably

moresevereformofNAFLDthancomparatormicewhohadonlybeenexposed

tothehighfatdietfromweaninguntiladulthood.Additionally,miceexposedto

gestational high fat diet had decreasedmitochondrial electron transport chain

function, suggesting that a stressor in early live has caused dysfunctional

mitochondria that are less efficient at preforming mitochondrial β‐oxidation,

predisposing the mouse to hepatic fat accumulation and programming the

development of NAFLD in adulthood. Another interesting pre‐natal factor

associated with the pathogenesis of paediatric NAFLD is the perturbation of

intrauterine environment during pregnancy. According to the “thrifty

phenotype” hypothesis, intrauterine growth retardation can lead to several

chronic conditionsandmetabolicdisorders (suchasNAFLD) later in life57.We

haveshownthatthe“smallforgestationalage”statewassignificantlyassociated

withsevereliversteatosis(NAFLDActivityScore>5)inchildhood58.Moreover,

inalargeepidemiologicalstudy,Sandbogeetal.hasalsoshownthatbodyweight

at2yearswasnegativelyassociatedwithNAFLD,afteradjustingforage,sexand

gestationalage.Thusthecurrentevidencetodatesuggeststhattheintrauterine

environmenthasthepotentialtohaveapowerfuleffectontheoffspring’sfuture

riskdevelopingNAFLDlaterinlife.

Study Methodology Findings

Ayonrindeet

al.,201759

N=1,170

Meanage17years

Prospective.USS‐diagnosed

NAFLD

NAFLDindependentlyassociatedwith:

Maternalpre‐pregnancyobesity

(OR2.3)

Breastfeeding64months(OR0.6)

Adolescentobesity(OR9.1)

Bugianesiet

al.,201758;

Nobilietal.,

200960;and

Nobilietal.,

200761

N=288

Meanage13years

Retrospective.Biopsy‐

diagnosedNAFLD

Low‐birthweightassociatedwith

increasedseveresteatosisand

portalinflammation,independentof

insulinresistance

Eachmonthofbreastfeeding

reducedNASH(OR0.7)andfibrosis

(OR0.9)

SGAassociatedwithinsulin

resistance

Suomelaet

al.,201623

N=2,042

Meanage42years.

Prospective.USS‐diagnosed

NAFLD

NAFLDindependentlyassociatedwith:

Pretermbirth(OR2.4)

Smallforgestationage(OR1.8)

Birthweight(OR0.8)

Insulinat11years(OR1.3)

Breijetal.,

201462

N=268

Meanage21years

Retrospective.FLI‐

diagnosedNAFLD

Rapidcatch‐upgrowthinthefirst3

monthsassociatewithhighFLI

score

NoassociationofFLIwithSGA

Sandbogeet

al.,201363

N=1,587

Meanage62years.

Retrospective.NAFLDliver

fatscore/equation‐

diagnosedNAFLD

Weightat2yearsnegatively

correlatedwithNAFLDscore

Lowweightat2yearswithlater

adultobesityhadhighriskof

NAFLD(OR19.5)

Fraseretal.,

200764

N=2,101

Meanage68years

Retrospective.Abnormal

LFT.

Birthweightnegativelycorrelated

withALT,GGT,andALP

Table1. Human evidence for pre‐natal and infant risk factors associatedwith

NAFLD.

Post‐natalfactors

Thepost‐natalfactorspredisposingtopaediatricNAFLDaresimilartothosefor

adult NAFLD and include common factors such as obesity, hyperinsulinaemia

andinsulinresistance.Inthepresenceofobesity,thepotentialforgoodadipose

tissue expansion is fundamental formaintaining lipid homeostasis and insulin

sensitivity and for protecting the lipid from increased lipid and inflammatory

fluxes that have the potential for promoting development and subsequent

progressionofNAFLD.When theprocessof the adipose tissueexpansion fails,

there is an associated low‐grade inflammation associated with adipocyte

autophagyandadipokineproduction.Inthislowgradeinflammatorystate,there

is increasedfluxoffreefattyacidsfromtheadiposetissuetothelivertogether

with increased pro‐inflammatory cytokines causing the recruitment of

macrophages in adipose tissue, stimulating the production of TNF‐α, IL‐6, and

reactive oxygen species and increasing adipocyte lipolysis65. In the liver, the

combined effect of free fatty acids and adipokines coming from the adipose

tissue, increases endoplasmic reticulum stress with consequent activation of

Kupffer cells; this triggers liver inflammation, potentially promoting

development of NASH66. This inflammatory state, triggers a cascade of

hepatocyteinjuryandincreasesoxidativestressandmitochondrialdysfunction

withconsequent impairmentof livermetaboliccapacity.Hyperinsulinemiaand

insulinresistancealsocontributetothedevelopmentofNAFLDinadolescenceas

duringpuberty,childrenexperienceaphysiologicalstateofinsulinresistance.In

a large cross‐sectional study, Moran et al. studied 357 healthy children and

adolescent who underwent hyperinsulinaemic‐euglycemic clamps. These

authors showed that there are significant differences in insulin resistance

between boys and girls; and that insulin resistance increases significantly at

Tannerstages2,3,4,butdecreasedtonearprepubertallevelsatTannerstage5.

Furthermore,whilst insulin resistancewas related toBMI and anthropometric

measures of fatness, these factors did not completely explain the insulin

resistance that occurs during the Tanner stages of puberty67. Moreover, in

further work, these authors showed there are sex‐related developmental

changes in insulin resistance,whichare independentof changes inadiposity68.

Duringthetransitionfromlatechildhoodthroughadolescence,insulinresistance

inmalesincreasedinassociationwithincreasedtriglycerideconcentrationsand

decreased high‐density lipoprotein cholesterol levels. This phenomenon was

noteddespiteaconcurrentreductioninbodyfatnessinmalechildren,whereas

theoppositeeffectwasobservedoccurredinfemalechildren.Itisinterestingto

speculatethatthesesex‐relateddevelopmentalchangesininsulinresistancemay

underpin,notonlydifferencesinNAFLDprevalencebetweenmalesandfemales

in adulthood, but also differences in cardiovascular risk between males and

femalesinadultlife.

Inchildhoodaphysiologicalstateofinsulinresistance,plusasedentarylifestyle

andtheconsumptionofunhealthyfood69mayincreaseobesity,decreaseskeletal

muscleoxidationoflipids,andpromotehepaticdenovolipogenesis(DNL).Inthe

presenceofhyperinsulinaemiathatisassociatedwithinsulinresistance,acetyl‐

CoAcarboxylaseisactivatedbyinsulinandacetyl‐CoAisconvertedintomalonyl‐

CoA,whichisthecommittedstepinhepaticfattyacidsynthesis.Therearetwo

important transcription factors that regulate DNL: sterol regulatory element‐

binding protein‐1 (SREBP‐1c) and carbohydrate response element‐binding

protein(ChREBP).Thesetranscriptionfactorsregulateenzymesinvolvedinfatty

acid and tri‐acyl glycerol synthesis. In addition, a high‐carbohydrate diet and

particularlyonethatcontainshighlevelsofdietaryfructosecanincreasehepatic

de novo lipogenesis by increasing substrate supply, and promoting the

expressionofSREBP‐1candChREBP70,71. DNL isanenergy‐expensiveprocess,

consuming7ATPand14NADPHtogenerateeachpalmitatefromacetyl‐CoA72.

Consistent with this, fructose causes hepatic ATP depletion with resultant

oxidativestressandpotentialformitochondrialdysfunction73,74.

Softicetal.investigatedthedifferentialeffectsofglucoseandfructoseinamouse

modelandshowedthattheadditionoffructosetoahighfatdietwasassociated

with: increased expression of SREBP‐1c and ChREBP, increased fatty acid

synthesis and also hepatic insulin resistance. In contrast, when glucose was

addedtothehighfatdiettheseauthorsfoundanincrease intotalChREBPand

livertriglycerideaccumulation,butnotinsulinresistance70,75(seeFigure1).In

thesamestudy,Softicetal.studiedhepaticexpressionofketohexokinase(KHK),

anenzymethatcatalysesthefirststepofintracellularfructosemetabolism76,in

bothmice and obese adolescents with NAFLDwhowere undergoing bariatric

surgery.Theseauthors found thatKHKexpressionwas increased2‐fold in the

mice whose high fat diet was supplemented with fructose. This finding

contrasted with their observations in mice whose high fat diet was

supplemented with glucose, where KHK expression did not increase

significantly. In the adolescents, KHK expression was 2‐fold higher in obese

patients with NASH, compared with obese patients without fatty liver. Thus,

thesedatasuggestthatdietaryfructoseisassociatedwithanincreaseexpression

ofKHKfavouringtheproductionofacyl‐CoAthatcontributestothedevelopment

of NAFLD through increased DNL75. The high activity of KHK contributes to

reducedcellularATPbyrapidphosphorylationoffructoseand,viare‐generation

ofATPinoxidativephosphorylation,hepatocytesbecomedepletedininorganic

phosphate. The net effect is elevated uric acid77 production, which has been

independentlyassociatedwithadvancedNASHhistologyinchildren13.

Hepaticoutcomes

Thelong‐termhepaticoutcomesofpaediatricNAFLDarenotclearduetoalack

of prospective natural history data and few children undergo paired biopsied.

The outcomes ofNAFLD in adults aremoredefined,wheredata demonstrates

that after over 30 years of follow‐up NAFLD is associated with increased all‐

cause mortality (hazard ratio (HR) 1.3) and hepatocellular carcinoma in (OR

6.6)30. Overall, liver‐related events occur in <10%of patientswithNAFLD but

thereisastrongcorrelationwithfibrosisstageandoutcome29.Inaddition,ithas

beensuggested that thereareagroupof ‘rapidprogressors’whomaydevelop

severefibrosiswithin5years78,thoughitremainstobeestablishedwhetherthis

isduetosamplingvariabilityonrepeatbiopsy.Liver‐relatedcausesofdeathare

thirdbehindcardiovasculardiseaseandnon‐hepaticmalignancy.

Thereareno robustdata todeterminewhether thisnaturalhistoryholds true

forpaediatricNAFLD.Itisalsonotwellestablishedwhatproportionofchildren

withNAFLDcontinuetohaveNAFLDasadults.Itisknownthataroundathirdof

obese adolescents will become obese adults79 but a follow‐up study from

paediatrictoadulttransitioninNAFLDhasnotyetbeenreported.

Feldsteinetal.reportedaretrospectivecohortof66childrenwithNAFLDwhere

two children underwent transplant for decompensated cirrhosis80. This study

has the longest follow‐up but its retrospective design and lack of data about

methodofdiagnosisaschildrenlimititsconclusions.Therehavebeenothercase

seriestosuggestthatseverefibrosisispossiblewhilststillachild81howeveritis

generallyregardedthatend‐stageliverdiseasewhilstunder16yearsisunlikely

to be secondary to NAFLD alone and should prompt a search for alternative

diagnoses82.Itisworthyofmentionthattherearesomespecificcircumstances,

particularly acquired hypothalamic‐pituitary insufficiency, that may be

associatedwithrapidprogressionoffibrosis83.

In adults, fibrosis is the solepredictorof long‐term liver‐relatedevents31.This

findinghasbeenreproducedinmultiplecohortsandnon‐invasivefibrosisscores

(NAFLD Fibrosis Score, Fib‐4, BARD) correlatewithmortality84.Whilst similar

scores exist in paediatric NAFLD (for example, the Paediatric NAFLD Fibrosis

Index85)itisnotknownwhethertheycorrelatewithlong‐termoutcome.

Datafromrandomisedcontrolledtrialsdemonstratesthatstage1and2fibrosis

is readily reversible within two years86,87. It is not known to what extent

advancedfibrosiscanregressinpaediatricNAFLD.

Therefore, toaccuratedetermine the long‐termhepaticoutcomes inpaediatric

NAFLD natural history studies are required. These have recently been

establishedbothsidesoftheAtlantic88,89andarelikelytorequiremorethan20

years follow‐uptoquantifyratesofhepatocellularcarcinomadevelopmentand

liverfailure.

Dangerousliaisons

There are several potential pit‐falls in the diagnosis, monitoring, and

managementofpaediatricNAFLD,whichwillbediscussedinthissection.

The most important point about diagnosing NAFLD in children is to exclude

conditionsmasqueradingasfattyliver.Itisrecognisedthatavarietyofliverand

systemicdisordersmaycausesecondarysteatosisincludingthoselistedintable

2.

SecondarycausesofNAFLD Test Abnormality

HepatitisB&C,EBV,CMV ViralhepatitisserologyIgGorIgMserology

positive

WilsondiseaseSerumcaeruloplasmin Lowlevels

Liverbiopsy Raiseddryweightcopper

AutoimmunehepatitisAutoantibodies PositiveANA/ASMA

Immunoglobulins IncreasedIgG

Alpha‐1‐antitrypsindeficiencyAlpha‐1‐antitrypsinlevels

andPitypePiZZ

Hereditaryhaemochromatosis SerumironstudiesRaisedferritinand

transferrinsaturation

Lipodystrophy,andother

insulin‐resistancesyndromes

ClinicalexaminationReducedsubcutaneous

adipose

Serumfastinginsulin Greatlyelevated

Lysosomalacidlipasedeficiency Drybloodspotassay ReducedLALactivity

Table2.Somesecondarycausesofhepaticsteatosisthatshouldbeexcluded

beforemakingadiagnosisofpaediatricNAFLD.

Schwimmer etal. presented strong evidence for liver biopsy in children with

suspected NAFLD. From 374 children referred from primary care, 255

underwent biopsy and 61 had a diagnosis other thanNAFLD,most frequently

autoimmune hepatitis. Children and adults with ‘lean’ NAFLD, with BMI and

waistcircumference<95%centile,maybemorelikelytohavesecondarycauses

for steatosisorNAFLD‐associatedpolymorphisms90. Invery leanchildrenwith

severeinsulinresistancelipodystrophyshouldbeconsidered91.

DifferentiatingWilson disease (WD) and NAFLDmay be very challenging and

somepaediatricianswouldarguethatbiopsyistheonlymethodtotrulyexclude

WD. Caeruloplasmin is a good screening test for WD and, depending on the

threshold used, may have a negative predictive value of 99% (Table 3)92.

However,asubsetofpatientsmayhavenormalcaeruloplasminandmissingthe

diagnosiscanresultinpermanentneurologicaldamage.Therefore,aliverbiopsy

withdryweightcopperimprovesthereliabilityofdiagnosis,butcangiveafalse

positive (for WD) as cholestatic disorders can cause copper accumulation82.

Molecular genetics can be used tomake a diagnosis ofWD but ATP7B can be

affected by a variety of mutations, therefore genetics cannot exclude the

diagnosis93.

Caeruloplasmin

concentration

cut‐off(g/L)

Sensitivity

(%)

Specificity

(%)

Positive

predictive

value(%)

Negative

predictive

value(%)

0.20 98 56 48 99

0.14 93 100 100 97

0.10 79 100 100 92

Table3.Dataonthevalidityofuseof3differentcut‐offthresholdsof

caeruloplasminfordiagnosisofWilsondiseaseinpatientsclinicallysuspectedof

havingthecondition.

Lysosomal acid lipase deficiency (LAL‐D), also known as cholesterol ester

storage disease, is a potential differential diagnosis for NAFLD. This rare,

autosomal recessive lysosomal disorder has a wide spectrum of clinical

presentation94.Wolmandiseaseisthemostsevereformwithrapidlyprogressive

liver failure in infants. A milder form presents in childhood or adults with

hepatic steatosis, raised aminotransferases, raised low‐density lipoprotein and

lowhigh‐densitylipoprotein.Diagnosisistheoreticallyimportantbecauseofthe

potential for treatmentwith sebelipase alfa95. However, despite the possibility

formisdiagnosisofLAL‐DasNAFLD,oraroleofLALinNAFLD96,todatethere

arenoreportsof identificationofLAL‐D incohortsof childrenwith fatty liver,

thereforeitsrelevancetoroutineclinicalpracticeremainstobeestablished.

It isnot clearhowbest tomonitorpaediatricNAFLD,but it iswell established

that aminotransferases are a poor marker of disease activity. ALT and AST

fluctuate throughout the disease course and do not correlate with fibrosis97,

thoughmay show some correlationwithNAFLDActivity Score38. Bloods often

become most abnormal during the relatively insulin resistant state of

adolescence98, therefore a reduction of ALT without evidence of weight loss,

shouldnotberelieduponasareassuringfinding.

Though the long‐term cardiovascular and metabolic outcomes of paediatric

NAFLDhaveyettobeformallyquantified,thesearelikelytothemainburdenof

disease for patients in adult life29,32. Therefore, hepatologists must remember

thatweight loss and improvement of insulin resistance is themost important

management goal, beyond the therapies targets at improving liver disease

activitydiscussedbelow.

Managementprogramme

The treatment of paediatric NAFLD can be divided into conservative,medical,

and surgical approaches. As alluded to above, the determinants of successful

management are not clear as the natural history of the condition is uncertain.

The goals are multi‐dimensional: improve the metabolic health of children to

reduce their long‐term cardiovascular risk, and reduce liver‐related clinical

events,presumablybytargetingfibrosis.Resultsfromthemajorcontrolledtrials

inpaediatricNAFLDaresummarisedinTable4.

Weight loss is the core therapy forpaediatricNAFLDand for all childrenwith

obesity99.Thismaybeachievedbydietarymodificationand/orphysicalactivity.

A variety of diets have been used in randomised and non‐randomised clinical

trials.Themostfrequentlyuseddietisa‘lowfat’hypocaloricdietatwith25‐30

kcal/kg,50‐60%carbohydrateand23‐30%fat(with1/3saturatedfat)87,100,101.A

recent systematic review of dietary and physical activity interventions found

thattherewasinsufficientevidencetosuggestanysinglemethodofweightloss,

butthatgreaterweightlossgavealargerimprovementinnon‐invasivemarkers

ofNAFLD102.Instudieswithbiopsyend‐points,areductioninage‐sex‐corrected

BMIisassociatedwithanimprovementinfeaturesofNASandfibrosis87.

There is recent physiological evidence to suggest that fructose restriction

improvesthemetabolicprofileofobesechildrenandpotential fortreatmentof

fattyliver12.Lowcarbohydrate103orlowfructose104dietshaveonlybeenusedin

pilot studies on paediatric NAFLD however there are several larger studies

planned105.

Trial n Intervention End‐points

Dietaryintervention

Vosetal.,2009104 10 Low‐fructosevslow‐fatdiet

Liverenzymes:noeffect

Ramon‐Kraueletal.,2013103

16 Low‐glycaemicloaddiet:vslow‐fatdiet

LiverenzymesandMRS:improvedbutnodifferencebetweengroups

Jinetal.,2014106 21Low‐fructosevsstandarddiet LiverenzymesandMRS:noeffect

Antioxidants

Vajroetal.,2004100

28 Lifestylevslifestyle+vitaminE

Liverenzymes:improvedbutnodifferencebetweengroupsUltrasound:unchanged

Nobilietal.,200887 53

Lifestylevslifestyle+vitaminE+vitaminC

Histologicalsteatosis,lobularinflammation,ballooning,andNAS:improvedbutnodifferencebetweengroups

Wangetal.,2008107 76

Nointerventionvsstrictlifestylevsunstructuredlifestyle+vitaminE.

Liverenzymes:improvedwithstrictlifestyleinterventionUltrasound:unchanged

Lavineetal.,201186 173

MetforminvsvitaminEvsplacebo

NASandballooningimprovedwithvitaminE.Liverenzymes:improvedbutnodifferencebetweengroups

Akcametal.,2011108

67Lifestylevslifestyle+metforminvslifestyle+vitaminE

Liverenzymes:improvedbutnodifferencebetweengroups

ShiasiAranietal.,2014109 119

MetforminvsvitaminEvsplacebo

Ultrasound:improvedbutnodifferencebetweendrugs

Schwimmeretal.,2016110

169 CBDRvsplacebo Lobularinflammation:improvedLiverenzymes:improved

Zohreretal.,2017111

40 Lifestylevslifestyle+DHA‐Cho‐VE

Liverenzymesandultrasound:improvedwithDHA‐Cho‐VEHistologicalimprovementinDHA‐Cho‐VE,butnobiopsyinplaceboforcomparison

Metformin

Nadeauetal.,2009112 50

Lifestylevslifestyle+metformin

Liverenzymes:improvedbutnodifferencebetweengroupsUltrasound:improvedwithmetformin

PolyunsaturatedfattyacidsNobilietal.,2013113 60 DHAvsplacebo

Liverenzymesandultrasoundsteatosis:improved

Boyrazetal.,2015101 108 Lifestylevslifestyle+PUFA

Liverenzymesandultrasound:improvedinlifestyle+PUFAgroup

Janczyketal.,2015114

76 DHA/EPAvsplacebo Liverenzymesandultrasound:improvedbutnodifferencebetweengroups

Pacificoetal.,2015115 51 DHAvsplacebo

Liverenzymes: improvedbutnodifferencebetweengroupsMRIhepaticfat:improved

DellaCorte,etal.,2016116 41 DHA+vitaminDvs

placebo

Liverenzymes:improvedHistologicalimprovementinDHA+VitD,butnobiopsyinplaceboforcomparison

ProbioticsVajroetal.,2011117 20 Lactobacillusvsplacebo

Liverenzymes:improvedUltrasound:unchanged

Alisietal.,2014118

44 Lifestylevslifestyle+VSL#3

Liverenzymes:unchangedUltrasound:improvedwithVSL#3

Famourietal.,2017119

64 Prokidprobioticvsplacebo

Liverenzymesandultrasoundsteatosis:improved

Bariatricsurgery

Mancoetal.,2017120 93

Sleevegastrectomyvsintragastricweightlossdevice(IGWLD)vslifestyle(non‐randomised)

FibrosisandNASH:improvedmostinsleevegastrectomy,andalsoinIGWLD

Table4.RandomisedcontrolledtrialsinpaediatricNAFLD.CBDR,

cysteaminebitartratedelayedrelease;DHA,docosahexaenoicacid;DHA‐Cho‐VE,

docosahexaenoicacidwithcholineandvitaminE;EPA,eicosapentaenoicacid;

IGWLD,intragastricweightlossdevice;PUFA,polyunsaturatedfattyacids;US,

ultrasoundscan;andVSL#3,aprobioticmixture.

However, it must be remembered, that even with close follow‐up in well‐

conducted clinical trials there is a relatively poor response to dietary and

physicalexciseinchildhoodobesity121.Complianceispoorandparticipantswith

low‐uptake of advice have greater rises in aminotransferases100. Therefore,

NAFLD should ideally bemanaged in amultidisciplinary clinic that includes a

dietician, clinical nurse specialist, and clinical psychologist to give the best

chanceofachievingweightloss.

There are no approved pharmacological therapies of paediatricNAFLD122. The

maingroupsofagentsthathavebeentestedtodateare:antioxidants,metformin,

poly‐unsaturatedfattyacids(PUFA),probiotics,andvitaminD.

AASLDguidance recommendsvitaminEas theonly therapy that ispotentially

efficacious in paediatric NAFLD99. This is primarily based on data from the

TONIC trial that demonstrated an improvement in ballooning and overall NAS

with vitamin E use, without any major adverse events123. Other studies have

usedvitaminEinavarietyofdosesanddurationsbuthavebeenlimitedbynot

usingprotocolledpairedbiopsies100,108,combinationtreatment87,111,ordiffering

weightlossbetweeninterventionarms107.Overall,vitaminEisprobablysafeand

mayimproveNASHactivity,thoughitremainstobeestablishedifthistranslates

intoimprovedliver‐relatedoutcomes.

Resultsfromarandomisedtrialofcysteaminebitartratedelayedrelease(CBDR)

have recently shownmodest improvements in lobular inflammation and there

wasoverallimprovementinhistologyinparticipantsweighingunder65kg124.It

acts by increasing intracellular glutathione,which then scavenges oxygen free

radicals.TheevidencebodyforCBDRissmallerthanthatforvitaminEanditis

likely that further studies will be required before it is incorporated into

guidelines.

Metformin has had more modest results, with some reports of improved

radiologicalevidenceofsteatosis112,109,butrandomisedbiopsydataislimitedto

that from the TONIC trial123. However, aside from its effects on the liver,

metforminmaybeusedbypaediatricendocrinologists in childrenwith insulin

resistanceatriskoftype2diabetes121,125.Atthistime,consensusguidelinesdo

notrecommendmetforminasaprimarytreatmentforNAFLDorNASH.

PUFA, mostly docosahexanoic acid (DHA) and eicosapentanoic acid, are given

with the aimof alerting the composition of the hepatic lipidome and reducing

lipotoxicity.Non‐invasivedataareencouraging,whereuseofatleast250mgper

dayfor6monthsmayresultinreductionofradiologicalsteatosisbutthereisno

biopsydataavailabletoconfirmthesefindings101,115,113.

Theevidenceofuseofprobioticsissimilar:avarietyofregimenshavebeenused

intrialsforpaediatricNAFLDbuttherearenostudieswithbiopsyend‐pointsto

date119,118. Although there is a large body of evidence that confirms the

association of intestinal dysbiosiswith obesity andNAFLD126–128, there is little

datatosupportmodulationofthemicrobiomeasaprimarytreatmentstrategy.

The associationof vitaminDdeficiencywithpaediatricobesity129,NAFLD, and

NASH130 is relatively well established and the use of replacement therapy in

deficient children is logical. Indeed, in children deficient in vitamin D,

replacement in combination with DHA does improve histology116. However, it

remains to be demonstratedwhether childrenwith acceptable 25‐OH‐D3 (>20

ng/L) benefit from supplementary vitamin D. In addition, the risk of

hypervitaminosisandresultingrenalimpairmentmustbeconsidered.

Finally,bariatricsurgeryisatreatmentoptionforseverepaediatricobesitywith

co‐morbidities. Expert consensus recommends that NAFLD should not be a

primaryindicationforweight‐losssurgeryhoweverevidencedoessuggestitto

be of use, with potential for reversal of fibrosis131,120. These findings are

consistent with data from adults, though there were insufficient un‐biased

studies for a Cochrane review to recommend it as a primary treatment132.

However, the long‐term data is clear that bariatric surgery improves the

metabolicandcardiovascularoutcomesforobeseindividuals133andthereforeit

may be part of the care for patientswith NAFLD. The psychological effects of

bariatricsurgeryarenottobeunderestimatedandthereisemergingdataonthe

impactthatsuchoperationshaveonpatientslaterinadultlife134.

Therefore, weight loss is the primary treatment of paediatric NAFLD and it

appearsthatthemethodbywhichthisisachieveddoesnotaffecttheoutcome.

Vitamin E is the only drug treatment thatmay be a direct hepatic benefit but

pharmacological management of the liver is a small component of the overall

careforchildrenwiththemetabolicsyndrome.

Implications&futuredirections

TheimplicationsofthesedataarethatpaediatricNAFLDisincreasingandthese

patientswillbecomeadultswithend‐stage liverdiseaseorHCC in10‐30years

time. Weight loss is the only intervention demonstrated to have significant

efficacy. Further investigation into the pathogenesis of paediatric NAFLD is

needed to complement translational studies with an aim to develop novel

therapeuticstrategies.Thereareonlyafewagentsintrialsinchildrenanddrug

developmentisprogressingatamuchslowerratethaninadults.

Future directionsmust focus on establishing on expanding our understanding

NAFLD pathogenesis with a translational therapy in mind. For example,

determiningthemicrobiomephylogenaassociatedwithlessseverefibrosisand

trialling probiotic therapy. It may also involve exploring whether recent

advancesinadulthepatologyarealsoapplicabletopaediatrics,suchastherole

ofVAP‐1ingut‐liveraxis,whichhasnotyetbeeninvestigatedinchildren.There

ismuchheterogeneityininvestigationsofNAFLD,particularlyinregardstouse

ofbiopsy,establishingbiomarkersthatcorrelatewithhistologyprogressionand

clinicaloutcomesremainsamajor target.Finally,despiteweight lossbeingthe

primarytreatmentforNAFLD,minimalprogresshasbeenmadeinguidanceon

determiningtheoptimalregimenoflifestylechanges.

In conclusion,despitemajor advances inunderstanding, research inpaediatric

NAFLDhasnot yet translated intopatient benefit. It is an important condition

with unmet scientific and clinical needs that requires urgent attention to slow

thefutureepidemicofend‐stageliverdiseaseinadults.

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