ClinicsandResearchinHepatologyandGastroenterology45(2021)101605
Availableonlineat
ScienceDirect
www.sciencedirect.comLETTER
TO
THE
EDITOR
Covid-19
and
hepatic
injury:
A
systematic
review
After observing patients with pneumonia of unknown
cause in Wuhan (China), a novel Coronavirus was
identi-fiedas2019novelcoronavirus(COVID-19).Gastrointestinal
symptomsarecommoninCOVID-19andcanbepresentinup
to26%ofpatientsinsomepopulations;themostcommonis
diarrhoea,followedbynauseaand/orvomitingand
abdom-inalpain.Afewstudiesrecentlydescribedliverimpairment
asacommonmanifestationofthevirus;therefore,a
corre-lationbetweentheseverityofthediseaseandliverinjury
isbeingsoughtup.
Previous studies showed that liver injury could be
detected using the elevated level of Alanine
Aminotrans-ferases (ALT), Aspartate Aminotransferase (AST), Total
Bilirubin(TBil)followedbyslightlydecreasedAlbumin
lev-els[1].AsunderlinedbyAl-Busafietal.theserumALTand
ASTarethebestmarkersofhepatocellularinjury,sotheir
elevatedvaluestendtoshowmoresevereliverdamage[2].
Liverinjuryisdefinedbyanincreaseofovertwicetheupper
limitofthenormalrange(2N)inserumalanine
aminotrans-ferase(ALT)orconjugatedbilirubin,oracombinedincrease
ofaspartate aminotransferase (AST),alkalinephosphatase
(AP),andtotalbilirubin,providedoneofthemisabove2N.
Several authors suggested that liver abnormalities in
COVID-19patients couldderivefromthepresence ofviral
infectioninlivercellsordrugtoxicityandsystemic
inflam-mation.
Mao et al. [3] elaborated a systematic review and
meta-analysisofemergingstudiesdescribing
gastrointesti-nalsymptomsandliverinjuryinCOVID-19patientswiththe
aimofquantifyingtheeffectsofthevirusonthedigestive
system. Theyanalyzed 35studies,including6686 patients
with COVID-19, mainly adult patients. The analysis of 12
studiesshowedapooledprevalenceofliverinjury,ALT,AST,
and TotalBilirubin respectively of 19%, 18%, 21% and 6%.
Ontheonehand,thepresenceofgastrointestinalsymptoms
seemedtobeassociatedwithsevereCOVID-19andwithboth
anincreasedriskofacuterespiratorydistresssyndromeand
liverinjury.Ontheotherhand,digestivecomorbiditiesdid
notdetermineanyriskofseveredisease.HighlevelsofALT,
ASTandtotalbilirubin,asindicesofliverdamage,wasfound
particularlyinpatientswithseveredisease[3,4].
The meta-analysis carried out by Zhu et al. [5]
sum-marizedtheclinicalandlaboratorycharacteristicsof8697
ChinesepatientswithCOVID-19,withtheaimofgaininga
better understanding of the disease for clinical decisions
andfutureresearch.Thestudyshowedasthemalegender
wasthe most represented (53,3%),fever andcough were
thetwomajorsymptoms,and,inparticular,abnormalliver
functionappearedin26,4%ofpatients[5].Inthereviewof
Xuetal.[6]abouttheriskfactorofcriticalillness
progres-sioninCOVID-19patients,bytheanalysisof20articles,it
emergedthat,amongthevariablesanalyzed,higherlevels
of alanine aminotransferase (ALT), aspartate
aminotrans-ferase(AST)andtotalbilirubin(Tbil)wereassociatedwith
severedisease.Moreover,thelevelsoflactate
dehydroge-nase(LDH),creatinekinase(CK)andd-dimer(D-D)increased
significantlyin severe patients. Sincecytokine storms are
involvedinCOVID-19disease,thestudyofabnormallevels
ofliverenzymesinpatientswiththisvirusmightbehelpful
toevaluatetheseverityofdisease.
Xinetal.[7]comparedtheriskofabnormalliverfunction
testsbetweensevereandnon-severe patientsaffectedby
thevirus.Theycollecteddatafromeightrecords,withan
overallsample sizeof7467 (2187withseverediseaseand
5280withanon-severedisease);theproportionofCOVID-19
patientswithabnormalALTandASTlevelswasrespectively
of29%and29,2%.Atthesametime,COVID-19patientswith
severediseaseturnedouttohave a37,1%ofincreaseALT
andin47,4%ofincreaseAST.Also,abnormalTBilvalueswas
found in18% of COVID-19patients andin 19,8%of severe
diseasepatients.Themeta-analysisclenchedtheideathat
theriskof elevatedALT,AST, TBilandLDHwashigherfor
severepatients than innon-severe ones [7].Parasaetal.
[8]intheirmeta-analysisandsystematic review,reported
dataaboutelevationofeitherASTorALTlevelsatthetime
ofpatients’clinicalpresentationfrom8studiesof23.
ThepooledprevalenceofelevatedALTlevelswas18,5%
ofpatientsandtheoneofASTlevelswas17,7%ofpatients,
whenincludingallstudies[8].Inmanyclinicalsurveys,liver
disfunctionhasbeenobserved,indicatingapossibilitythat
in patients with COVID-19 this may cause hepatic injury.
Samidoustetal.[1]reportedanoccurrenceofliverinjury
https://doi.org/10.1016/j.clinre.2020.101605
LETTERTOTHEEDITOR
Table1 LivertestsabnormalitiesinpatientswithSARSCoV-2infection. Reference Samplesize ElevatedALT
value ElevatedAST value ElevatedTBil value Abnormal coagulation factors Prevalenceof liverinjuryin severe disease Maoetal.[3] 1267 ALT(18%) AST(21%) TBil(6%) NA Yes Zhuetal.[5] 8697 Yes Yes Yes D-dimer(20,4%) NA
Xuetal.[6] 4062 Yes Yes Yes D-dimer Yes
Xinetal.[7] 7467 ALT(29%) AST(29,2%) TBil(18%) NA Yes Parasaetal.[8] 4805 ALT(18,5%) AST(17,7%) NA NA Yes(39,4%)
Samidoustetal.[1] 4191 Yes Yes Yes NA Yes
asacomplicationofCOVID-19,ranged from14,8%to53%.
It wasaccompanied by abnormalALT/AST levels followed
byelevated bilirubinlevels.Inaddition,theproportionof
liver injury in death cases and severe COVID-19 patients
was higher than that in mild patients. The meta-analysis
included4191COVID-19patientsand288deathcases.The
prevalenceofliverinjurywas19,5%,insteadamongthe288
deathcasestheprevalenceofliverinjurywas22,8%.Liver
damagehasbeenconsideredasanimportantriskfactorfor
severeoutcomesanddeathinsomeviralinfectionsincluding
MERSandSARS[1](Table1).
The descriptive study of Chen et al. [4] detected 49
patientswithCOVID-19,agreatpartofthemreportedorgan
functionsdamageand43patientsshoweddifferingdegrees
ofliverfunctionabnormality,withALTorASTabovethe
nor-mal range,inparticular onepatientpresented severliver
functiondamage,withALT7590U/LandAST1445U/L[4].
Abnormalities in liver chemistries, including aspartate
transferase(AST),alaninetransferase(ALT),andtotal
biliru-bin (TBil), has been described since early observational
studies.Thesedataareparticularlyevidentinpatientswith
COVID-19andseverediseases.
The directassault ofSARS-CoV-2 onhepatocytes could
be the firstreason thatleads toabnormalvalues of liver
enzymes.Evenifitseemedthathepatocytesdidn’texpress
high-levelofACE2,instead,theexpressionofhighlevelof
ACE2incholangiocytescouldrepresentanindirectcauseof
elevatedliverenzymes,aswellasacholangiocyte
dysfunc-tion.Againstthishypothesis,alkaline phosphatasehasnot
beenshowntobehighinCOVID-19patients.
Several pro-inflammatory factors reach the liver via
bloodcirculation,whichcanactivateKupffercellsandlead
tomoreIL-6release.IL-6is, in particular,closely related
toliverinjury insevere COVID-19patients [7].Lastly,the
occurrenceofSARScanleadtohypoxicinjury,mainlycaused
byseverepneumoniaanddrug-related, andtosubsequent
liverdysfunction.
A multicenter study in Chinese adults with COVID-19
pneumonia [9] reporteda dynamic pattern of liverinjury
indicators, withafirstincrease ofAST,followedbyALT in
severepatientsandmildfluctuationsoftotalbilirubinlevels
independentlyfromdiseaseseverity.InthisstudyAST
lev-elswere significatively associatedwiththemortality risk.
Despite the absence of a severe cholestatic pattern
dur-ing COVID-19disease, hyperbilirubinemia wasobserved in
11%—18%ofcases[10].
Therefore,recentstudiessuggestthatliverbiochemical
indicatorsmaybeusedaspredictorsofseverityand
progno-sisofCOVID-19patients.Inthefuturetheycouldbeusedas
earlymarkersofexacerbationanddeteriorationofpatients
withthedisease.
Disclosure
statement
Theauthorshavenothingtodisclose.
Declaration
of
interests
The authors declare that they have no known competing
financialinterestsorpersonalrelationshipsthatcouldhave
appearedtoinfluencetheworkreportedinthispaper.
References
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[10] Portincasa P, Krawczyk M, Machill A, Lammert F, Di
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http://dx.doi.org/10.1016/j.ejim.2020.05.035. FrancescoSerraa,∗ IsabellaBonaducea NicolaDeruvoa NicolaCauteroa LucioBrugionib RobertaGelminia
aDepartmentofSurgery,UniversityofModenaandReggio
Emilia—–PoliclinicoofModena,ViadelPozzo,7141100 Modena,Italy
bDepartmentofEmergencyMedicine,Universityof
ModenaandReggioEmilia—–PoliclinicoofModena,Viadel Pozzo,7141100Modena,Italy
∗Correspondingauthor.
E-mailaddresses:serrafrancescomd@gmail.com(F.Serra),
bellabonaduce@libero.it(I.Bonaduce),
Deruvo.nicola@aou.mo.it(N.Deruvo),
cautero.nicola@aou.mo.it(N.Cautero),
brugioni.lucio@aou.mo.it(L.Brugioni),
roberta.gelmini@unimore.it(R.Gelmini)
