Nutraceutical Approach to Non-Alcoholic Fatty Liver Disease (NAFLD)

18 Pages·2017·1.74 MB·English

nutrients
Review
Nutraceutical Approach to Non-Alcoholic Fatty Liver
Disease (NAFLD): The Available Clinical Evidence
ArrigoF.G.Cicero1,* ID,AlessandroColletti1andStefanoBellentani2
1 ItalianSocietyofNutraceuticals(SINut),MedicalandSurgicalScienceDepartment,UniversityofBologna,
40138Bologna,Italy;[email protected]
2 GastroenterologyandHepatologyService-ClinicaSantaChiara,6604Locarno,Switzerland;
[email protected]
* Correspondence:[email protected];Tel.:[phone]
(cid:1)(cid:2)(cid:3)(cid:1)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:1)
(cid:1)(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)
Received:15July2018;Accepted:21August2018;Published:23August2018
Abstract: Non-alcoholicfattyliverdisease(NAFLD)isaclinicalconditioncharacterizedbylipid
infiltrationoftheliver,highlyprevalentinthegeneralpopulationaffecting25%ofadults,witha
doubledprevalenceindiabeticandobesepatients. Almost1/3ofNAFLDevolvesinNon-Alcoholic
SteatoHepatitis(NASH),andthiscanleadtofibrosisandcirrhosisoftheliver. However,themain
causes of mortality of patients with NAFLD are cardiovascular diseases. At present, there are
no specific drugs approved on the market for the treatment of NAFLD, and the treatment is
essentially based on optimization of lifestyle. However, some nutraceuticals could contribute to
theimprovementoflipidinfiltrationoftheliverandoftherelatedanthropometric,haemodynamic,
and/orbiochemicalparameters. Theaimofthispaperistoreviewtheavailableclinicaldataonthe
effectofnutraceuticalsonNAFLDandNAFLD-relatedparameters. Relativelyfewnutraceutical
moleculeshavebeenadequatelystudiedfortheireffectsonNAFLD.Amongthese,wehaveanalysed
indetailtheeffectsofsilymarin,vitaminE,vitaminD,polyunsaturatedfattyacidsoftheomega-3
series,astaxanthin,coenzymeQ10,berberine,curcumin,resveratrol,extractsofSalviamilthiorriza,
andprobiotics. Inconclusion,Silymarin,vitaminEandvitaminD,polyunsaturatedfattyacidsof
the omega-3 series, coenzyme Q10, berberine and curcumin, if well dosed and administered for
medium–longperiods,andassociatedtolifestylechanges,couldexertpositiveeffectsonNAFLD
andNAFLD-relatedparameters.
Keywords: NAFLD;dietarysupplements;nutraceuticals;clinicaltrials
1. Introduction
Theliveristhelargestglandinthehumanbody. Ithasanantrophrenicaction(bothendocrine
and exocrine) and more than 150 other functions. In particular, the liver interacts with the
glyco-lipidmetabolism,beingresponsibleforgluconeogenesis,glycogenolysis,glycogenosynthesis,
apolipoprotein synthesis, cholesterol, and triglycerides, and Low-Density Lipoprotein (LDL)
cholesterol elimination through biliary route. The bile produced by the liver is also essential for
emulsifyinglipidsintheintestineallowingabsorption. Theliverisalsoresponsibleformaintaining
plasmaosmolarity,throughtheproductionofalbuminandglobulins,fortheproductionofcoagulation
factors,suchasfactorI(fibrinogen),II(thrombin),V,VII,IX,X,XI,andotherproteinsinvolvedin
coagulationprocesses,suchasproteinC,proteinS,hepcidin,andantithrombin. Inadditiontothese,
italsoproducesotherproteinsandenzymesessentialforsurvival(e.g.,alpha-1antitrypsin). Theliver
isalsoresponsibleforthecatabolismofendogenoustoxicants,forthestorageofglycogen,vitamin
B12,ironandcopper,anditmainlycontributestothefunctionoftheimmunesystem. Forallthese
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reasons,itisevidentthatliverhealthisessentialformaintenanceofthehealthoftheentireorganism
andmustbepreservedasmuchaspossible[1].
Intracellularinfiltrationoffatintheliveriscalledliversteatosisandcouldbeduetobothexcessive
alcoholintake(AlcoholicFattyLiverDisease—AFLD)andothermetabolicfactors(Non-Alcoholic
FattyLiverDisease—NAFLD).TheinternationalthresholdlevelchosenbytheScientificCommunity
todistinguishAFLDfromNAFLDis2drinks,theequivalentof20g,perday. NAFLDisanextremely
commonconditionaffecting25–30%ofthegeneraladultpopulation,15%ofchildren,andmorethan
50%ofoverweight,obese,andtype2diabetics. NAFLDcouldnotbeconsideredarealdiseaseevenif
absolutelyreversible[2].
TheclinicallyaggressivevariantofNAFLD,non-alcoholicsteatohepatitis(NASH),characterized
byinflammationandprogressivetissuedegeneration,affectsabout5%ofthegeneraladultpopulation,
and 20% of obese people [3]. The gold standard for NAFLD and NASH diagnosis is liver biopsy.
However,thediagnosisofNAFLDisusuallymadebyultrasounds(“brightliver”),afterexcluding
other causes of chronic liver disease, an alcohol intake lower of 20 g/day, and by using validated
scores,suchastheFattyLiverIndex(FLI),orfibrosisscoreorothers[4].
ThemainriskfactorsforprimaryNAFLandNAFLD(Table1)areoverweight/obesity,insulin
resistance/type 2 diabetes, hypertriglyceridaemia and the related dietary-behavioural triggers,
primarily the intake of beverages sweetened with fructose. By itself, in different observational
studies [5], only consumption of sugared soft drinks (mainly with fructose) increases the risk of
developingNAFLDofaround55%[6]. Amongtheemergingriskfactorstherearealsothesmoking
habitandtheObstructiveSleepApnoeaSyndrome(OSAS),butalsoinsomniaandexcessivedaytime
sleepinessunrelatedtonocturnalsleepapnoea[7,8]. However,thefirstriskfactorisoftenrelatedto
poorlifestylehabits. Finally,thestrongassociationbetweenhypothyroidismandNAFLDhasrecently
been confirmed by a meta-analysis of 13 prospective studies that showed how hypothyroidism
could increase the risk of NAFLD to more than 50%. The risk increases up to 70% if subclinical
hypothyroidismisexcluded[9].
Table1.MainriskfactorsforthedevelopmentofNon-AlcoholicFattyLiverDisease(NAFLD).
Defined Emerging
Dietrichinrefinedfoods,carbohydrateswithahigh Sarcopenia
glycemicindex,drinkssweetenedwithfructose Hypothyroidism
Sedentary Hyperuricemia
Overweight/Obesity Cigarettesmoke
Insulinresistance/TypeIIdiabetes Chronicobstructivepulmonarydisease(COPD)
Intakeofcortisones,methotrexate,some Polycysticovarysyndrome
antiretrovirals Helicobacterpyloriinfection
NAFLDisthefirststepforthedevelopmentofirreversiblealterationsoftheliverparenchyma
leadingtocirrhosis(about1/3ofthecasesofNAFLDtendtobecomeNASH,and15%ofthesecan
degenerateintocirrhosis),whileontheotherhand,NAFLDisitselfariskfactorforthedevelopment
ofcardiovasculardisease[10]andtype2diabetes,andpreliminarydatasuggestthatitmayalsobe
associatedwithagreaterincidenceofhepaticandextra-hepaticoncologypathologies[11]. Arecent
meta-analysis of 9 observational studies that included data from 96,595 adult subjects (34.1% of
whomwereaffectedbyNAFLD)with4654casesofmoderate-to-severerenalfailureoveramedian
observationperiodof5.2yearsshowedariskofalsodevelopingchronicrenalfailure37%higherin
patientswithNAFLD.Thisriskwasthegreaterthedegreeoflipidinfiltrationoftheliver. Considering
thatbothrenalfailureandNAFLDinthemselvesarethenriskfactorsforcardiovasculardisease,itis
easytounderstandhowthisepidemiologicalassociationisofparticularrelevance[12].
Anothermeta-analysisofsixstudiesthatincluded25,837patients(ofwhom5953wereaffected
byNAFLD)showedthatpatientswithNAFLDhadarelativeriskoftotalcardiovasculareventsof
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1.77(95%CI1.26–2.48,p<0.001). Specifically,therelativeriskincreasedto2.26(95%CI:1.04–4.92,
p<0.001)withregardtocoronaryarterydiseaseandto2.09(95%CI:1.46–2.98,p<0.001)relativeto
ischemicstroke. Furthermore,thepresenceofNAFLDseemstosignificantlyincreasetherelativerisk
ofmortalityduetocardiovascularcauses(RR1.46,95%CI1.31–1.64,p<0.001)[13].
Pendingspecificdrugtherapies,actuallyinphase3clinicaltrials,themaintreatmentofNAFLD
iscurrentlytheimprovementoflifestyleaimedatweightlossandincreasedphysicalactivities, in
ordertoreduceinsulinresistance[14]. SincetheriskfactorsforNAFLDaresimilartotheonesfor
cardiovasculardiseases,thesuggestionsforthemanagementofNAFLDarethesamesuggestedbythe
guidelinesforthepreventionofcardiovasculardiseases[15]. Therefore,thegeneralindicationisto
prescriberelativelylow-caloriediets(withacaloricquantityproportionaltoenergyconsumption),
with carbohydrates predominantly with a low glycemic index and minimizing the consumption
of fructose, alcohol, saturated and trans-unsaturated fats [16]. In particular, the adherence to
Mediterranean Diet is a significant predictor of changes in the fat content of the liver in patients
withNAFLD[17]. Theconsumptionofcoffeewillnotbeprescribedbutifconsumedbythepatientit
willnotbesuggestedtoquitit,sincetherearemanyevidences,summarisedinarecentmetanalysis,
showingalowerriskoffibrosisincoffeedrinkerswithNAFLD[18].
Theroleofphysicalactivityisfundamental,tobeimplementedasmuchaspossibleaccording
tothedegreeoftrainingandanyco-morbidities. Infact,arecentmeta-analysisof6cohortstudies
involving142,781participantswith32,657incidentcasesofNAFLD,aswellas4case-controlstudies
involving 382 affected patients and 302 controls, shows that the difference in risk of developing
NAFLDamongsedentaryandphysicallyactiveis21%inobservationalstudiesand57%incase-control
studies[19]. Ontheotherhand,regardlessofdiet,thegreaterthefrequencyandintensityofphysical
activity,thegreaterthereductionoftransaminaselevelsandthedegreeofhepatosteatosis,especially
inoverweightsubjects[20].
Tothisdutifulapproach,increasingevidencesuggeststhattheprescriptionofspecificsupplements
or nutraceuticals with demonstrated hepatoprotective action can be suggested to accelerate the
improvement of the alteration of liver enzymes and maybe of liver steatosis or at least to slow
downitsevolution[9]. Thisrationalebecomesstrongerwhenusingnutraceuticalssimultaneously
activeonthemodulationofcardiovascularrisk.
2. Methods
For the purpose of this review, a systematic search strategy was developed to identify trials
inbothMEDLINE(NationalLibraryofMedicine,Bethesda,Maryland,MD,USA;January1980to
May2018)andtheCochraneRegisterofControlledTrials(TheCochraneCollaboration,Oxford,UK).
The terms ‘nutraceuticals’, ‘dietary supplements’, ‘food bioactives’, ‘herbal drug’, ‘liver steatosis’,
‘non-alcoholicfattyliverdisease’,‘NAFLD’,‘clinicaltrial’,and‘human’wereincorporatedintoan
electronicsearchstrategy. Thereferencesofallidentifiedstudiesandreviewarticleswerereviewed
tolookforadditionalstudiesofinterest. Theauthorsreviewedallofthecitationsretrievedfromthe
electronicsearchtoidentifypotentiallyrelevantarticlesforthisreview. Weexcludedinvitrodata
andanimalstudiesandfocusedonhumandata,inordertolimitourreporttofoodcomponentsand
nutraceuticalsforwhichsafetyandtolerabilityinhumansarealreadyknown. Therefore,wepreferably
selectedpapersreportingrecentcomprehensivereviewsormeta-analyses,ororiginalclinicaltrialson
substanceswithalipid-loweringeffectandthoseimprovingactiononvascularhealth.
3. Results
Froma“nutraceuticalpointofview”, therearerelativelyfewmoleculesadequatelyclinically
studiedfortheireffectsonNAFLD:amongthese,wewillanalyseindetailtheroleofsilymarin,vitamin
E,vitaminD,polyunsaturatedfattyacidsoftheomega-3series,astaxanthin,coenzymeQ10,berberine,
curcumin,resveratrol,extractsofSalviamilthiorriza,andprobiotics.
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3.1. Silymarin
3.1. Silymarin
Silymarinisapowerfulantioxidantagentextractedfrommilkthistle(Silybummarianum)with
Silymarin is a powerful antioxidant agent extracted from milk thistle (Silybum marianum) with a
a specific liver tropism. Silymarin is actually a set of antioxidant substances of which the most
specific liver tropism. Silymarin is actually a set of antioxidant substances of which the most
concentratedaresixflavolignans(silibineAandB—usuallyinisoconcentration—,isosilibine,silidianin,
concentrated are six flavolignans (silibine A and B—usually in isoconcentration—, isosilibine,
silicristine, isosilicristine) and a flavonoid (taxifolin) [21]. Of these substances, the one with the
silidianin, silicristine, isosilicristine) and a flavonoid (taxifolin) [21]. Of these substances, the one with
highestconcentrationandthemostevidentbiologicaleffectsissilybin(Figure1),(IDIUPAC:(2R,3R)
the highest concentration and the most evident biological effects is silybin (Figure 1), (ID IUPAC: (2R, 3R)
-3,5,7-trihydroxy-2-(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo
-3,5,7-trihydroxy-2-(2R, 3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl) -2,3-dihydrobenzo
[b][1,4]dioxin-6-yl]chroman-4-one,molecularmass482,44g/mol),constitutingupto70%ofsilymarin
[b] [1,4] dioxin-6-yl] chroman-4-one, molecular mass 482,44 g/mol), constituting up to 70% of
initsdiastereoisomericsilybinAandsilybinBforms[22].
silymarin in its diastereoisomeric silybin A and silybin B forms [22].
Figure 1. Chemical structure of silybin.
Figure1.Chemicalstructureofsilybin.
Silymarin has poor oral bioavailability, both due to poor intestinal absorption and high hepatic
Silymarinhaspoororalbioavailability,bothduetopoorintestinalabsorptionandhighhepatic
first-pass metabolism. However, this limitation can be bypassed with particular pharmaceutical
first-pass metabolism. However, this limitation can be bypassed with particular pharmaceutical
techniques, for example by complexing silymarin in a phytosome with phosphatidylcholine, which
techniques, for example by complexing silymarin in a phytosome with phosphatidylcholine,
increases its solubility while maintaining its antioxidant properties [23]. Silymarin is undoubtedly
which increases its solubility while maintaining its antioxidant properties [23]. Silymarin is
one of the most studied nutraceuticals of plant origin in hepatopathic patients, even with severe
undoubtedlyoneofthemoststudiednutraceuticalsofplantorigininhepatopathicpatients,evenwith
disease [24]. The pharmacological mechanisms by which silymarin exerts its hepatoprotective action
severedisease[24]. Thepharmacologicalmechanismsbywhichsilymarinexertsitshepatoprotective
in patients with NAFLD are numerous and summarized in Table 2 [25], which also highlights those
actioninpatientswithNAFLDarenumerousandsummarizedinTable2[25],whichalsohighlights
that could have a positive impact on vascular health.
thosethatcouldhaveapositiveimpactonvascularhealth.
Table 2. Biological effects of silymarin involved in its hepatoprotective action in patients with
Table2.BiologicaleffectsofsilymarininvolvedinitshepatoprotectiveactioninpatientswithNAFLD.
NAFLD.
Effect ProposedMechanismofAction
Effect Proposed Mechanism of Action
• Directscavengeractivity*
Antioxidant •• MitDocihroencdtr isaclafuvnectniogneorp taimctiizvatiitoyn **
• ActivationofprotectivemoleculessuchasHeatShockProteins,thioredoxinandsirtuins
• Mitochondrial function optimization *
Antioxidant • InhibitionofNF-κBactivity
Anti-inflammatory •• ProAinflcatimvmaattioorny coyfto pkirnoetseycntthiveseis mredoulcetciounl(eILs- 1s,uILc-h6, aTsN FH-αe,aTtN SFh-βo)c*k Proteins,
Anti-apoptotic •thiMoroedduloatxioinno afncadsp sasiretruelienasse andTNF-αeffect
• Inhibitionoftheconversionofstellatecellsintofibroblasts
Antifibrotic •• DowInnhreigbuiltaitoionn oofft hNeeFx-pκreBs saiocntiovfiptryofi broticgenes(procollagenIII,TGF-β)
Anti-inflammatory •• ParPtiarloaicntifvlaatimonmofaetsotrroyge ncyretcoekptionrse *synthesis reduction (IL-1, IL-6, TNF-α,
• Insulin-sensitizingaction*
TNF-β) *
Endocrine-metabolic • PPAR-agonistaction*
Anti-apoptotic •• IncMreaosdeduelxaptrieosnsio onfo cfaGsLpUaTs4eo nrethleecaeslles uarnfadce T*NF-α effect
• InhibitionofHydroxy-Methyl-GlutarylCoenzymeAreductase*
Choleretic •• UprIenghuliabtiiotnioonft hoef btihlees acltoenxvpoerrtspiuomnp o*f stellate cells into fibroblasts
GLUT4=glucosetransportertype4, IL=Interleukin, NF-κB=nuclearfactorkappa-light-chain-enhancerof
Antifiabctriovtaitced Bcells,PPAR=•p eroxiDsoomwenprroelgifuerlaattoiro-anc toivf atthede reexcepprteosr,sTioGnF -oβf= ptrroanfisbforromtiinc gggernoewst h(pfarcotocroblleatag,en
TNF=tumornecrosisfactoIIr,I*, pToGteFn-tβia)ll ypositiveeffectsonvascularhealth.
• Partial activation of estrogen receptors *
Theavailabledatashowtheabilityofsilymarin(administeredalone,orusuallyincombination
• Insulin-sensitizing action *
withlowdosagesofvitaminE)toimproveinsulinresistanceandindirectmarkersofhepatosteatosis
Endocrine-metabolic • PPAR-agonist action *
(HepaticSteatosisIndex,LipidAccumulationProduct)alreadyafter3monthsoftreatment[26].
• Increased expression of GLUT4 on the cell surface *
• Inhibition of Hydroxy-Methyl-Glutaryl Coenzyme A reductase *
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Choleretic • Upregulation of the bile salt export pump *
GLUT4 = glucose transporter type 4, IL = Interleukin, NF-κB = nuclear factor kappa-light-chain-
enhancer of activated B cells, PPAR = peroxisome proliferator-activated receptor, TGF-β =
transforming growth factor beta, TNF = tumor necrosis factor, * potentially positive effects on vascular
health.
The available data show the ability of silymarin (administered alone, or usually in combination
Nwuittrhie nltosw20 1d8o,1s0a,g1e1s5 3of vitamin E) to improve insulin resistance and indirect markers of hepatostea5toofs1i8s
(Hepatic Steatosis Index, Lipid Accumulation Product) already after 3 months of treatment [26].
In a recent multicenter randomized double-blind phase 3 study conducted on 180 patients with
In a recent multicenter randomized double-blind phase 3 study conducted on 180 patients
histological diagnosis of NAFLD/NASH, the administration of silybin and vitamin E (silibine 188 mg,
withhistologicaldiagnosisofNAFLD/NASH,theadministrationofsilybinandvitaminE(silibine
phosphatidylcholine 388 mg, vitamin E 180 mg) for 12 months determined the normalisation of
188mg,phosphatidylcholine388mg,vitaminE180mg)for12monthsdeterminedthenormalisationof
transaminase, a significant reduction of gamma-glutamyl transferase levels and the significant
transaminase,asignificantreductionofgamma-glutamyltransferaselevelsandthesignificantdecrease
decrease of liver steatosis measured with both ultrasound scan and, in one-fifth of patients, with a
ofliversteatosismeasuredwithbothultrasoundscanand,inone-fifthofpatients,withasecondliver
second liver biopsy. As expected, there was also a proportional improvement of fasting glucose, basal
biopsy. Asexpected,therewasalsoaproportionalimprovementoffastingglucose,basalinsulinemia
insulinemia and insulin resistance index [27]. These data were confirmed by a meta-analysis of 8
andinsulinresistanceindex[27]. Thesedatawereconfirmedbyameta-analysisof8controlledclinical
controlled clinical trials involving 587 patients [28]. There is also a preliminary report showing that
trialsinvolving587patients[28]. Thereisalsoapreliminaryreportshowingthatsupplementation
supplementation with 420 mg/day of silymarin reduced the 4-years risk of mortality in patients with
with 420 mg/day of silymarin reduced the 4-years risk of mortality in patients with cirrhosis [29].
cirrhosis [29]. Overall tolerability is usually good, even for high doses and long-term administration
Overalltolerabilityisusuallygood,evenforhighdosesandlong-termadministration[30]. Forthese
[30]. For these reasons, the guidelines of the Mayo Clinic on food supplements classifies the use of
reasons, the guidelines of the Mayo Clinic on food supplements classifies the use of silymarin for
silymarin for hepatoprotection as Grade B (“Good scientific evidence for this use”) [31].
hepatoprotectionasGradeB(“Goodscientificevidenceforthisuse”)[31].
Of particular interest from a cardiometabolic point of view is the clinical effect of silymarin on
Ofparticularinterestfromacardiometabolicpointofviewistheclinicaleffectofsilymarinon
the metabolic control of the diabetic patient. A recent meta-analysis of five controlled clinical trials
themetaboliccontrolofthediabeticpatient. Arecentmeta-analysisoffivecontrolledclinicaltrials
that enrolled 270 patients showed how the administration of silymarin significantly improved fasting
thatenrolled270patientsshowedhowtheadministrationofsilymarinsignificantlyimprovedfasting
glycemic control (−26.86 mg/dL; 95% CI −35.42–18.30) and glycated hemoglobin values (−1.07; 95%
glycemiccontrol(−26.86mg/dL;95%CI−35.42–18.30)andglycatedhemoglobinvalues(−1.07;95%
CI −1.73–0.40), plausibly for the insulin-sensitizing action of this nutraceutical [32].
CI−1.73–0.40),plausiblyfortheinsulin-sensitizingactionofthisnutraceutical[32].
The greatest limitation in the use of silymarin is usually the cost of effective dose treatment,
Thegreatestlimitationintheuseofsilymarinisusuallythecostofeffectivedosetreatment,which
which needs to be administered continuously and protracted over time at least until optimisation of
needs to be administered continuously and protracted over time at least until optimisation of the
the lifestyle, and normalisation of ultrasound liver scan.
lifestyle,andnormalisationofultrasoundliverscan.
33..22.. VViittaammiinn EE
AA nuntruatcreaucetiucatilc atlestedte setexdtensiveexltye nisniv eplaytientisn witpha tNieAntFsLD, wailtthhougNh AaFlLmDo,st aalwltahyosu gihn
aalsmsoocsiattioanl wwaiyths siilnymaarsinso, ciisa tvioitnamiwn iEth (alspihlyam-toacroinp,heriosl ovr i(t2aRm)i-n2,5,7E,8-T(eatlrpahmae-ttohcyolp-2h-[e(r4oRl,8Ro)r-
((24R,8),-122,5-t,r7i,m8-eTtehtyraltmriedtehcyyll-)2]-c[h(4roRm,8Ran)--(64-,o8l,)1 2(F-tirgiumreet 2h)y. ltridecyl)]chroman-6-ol)(Figure2).

Figure 2. Chemical structure of tocotrienols.
Figure2.Chemicalstructureoftocotrienols.
The most effective dosage of the active form of Vitamin E in order to reduce inflammation and
The most effective dosage of the active form of Vitamin E in order to reduce inflammation
liver fibrosis is 40 times higher than the Recommended Daily Allowance (RDA) (800 IU/day).
andliverfibrosisis40timeshigherthantheRecommendedDailyAllowance(RDA)(800IU/day).
However, doses 20 times higher (400 IU/day) are associated with increased risk of mortality from all
However,doses20timeshigher(400IU/day)areassociatedwithincreasedriskofmortalityfromall
causes. Therefore, caution is necessary to set up long-term therapies with vitamin E at the effective
causes. Therefore,cautionisnecessarytosetuplong-termtherapieswithvitaminEattheeffective
dosage. The majority of clinicians use Vitamin E either at a lower, less-effective, but safer dosages or
dosage. ThemajorityofcliniciansuseVitaminEeitheratalower,less-effective,butsaferdosagesor
by associating it with other active drugs that are probably effective in the management of NAFLD
byassociatingitwithotheractivedrugsthatareprobablyeffectiveinthemanagementofNAFLD[33].
[33]. A recent meta-analysis of 16 controlled clinical trials has shown that the long-term
Arecentmeta-analysisof16controlledclinicaltrialshasshownthatthelong-termadministrationof
administration of low-dose Vitamin E and alone (not in association with other antioxidant vitamins)
low-doseVitaminEandalone(notinassociationwithotherantioxidantvitamins)isabletoreduce
is able to reduce the risk of myocardial infarction (RR 0.82; 95%CI, 0.70–0.96; p = 0.01) [34].
the risk of myocardial infarction (RR 0.82; 95%CI, 0.70–0.96; p = 0.01) [34]. Furthermore, another
meta-analysisinvolving303subjectsenrolledinsevenstudiesshowedthatvitaminEsupplementation
isassociatedwitha2.5%increaseinflow-mediatedvasodilatation[35]. Thisresultisimportantsinceit
hasbeenestimatedthata1%improvementinflow-mediatedvasodilatationwouldbeassociatedwith
a12%reductionincardiovascularrisk[36].
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Furthermore, another meta-analysis involving 303 subjects enrolled in seven studies showed that
vitamin E supplementation is associated with a 2.5% increase in flow-mediated vasodilatation [35].
NTuhtirsie nrtess2u01l8t ,1is0 ,1im153portant since it has been estimated that a 1% improvement in flow-med6iaotfe1d8
vasodilatation would be associated with a 12% reduction in cardiovascular risk [36].
3.3. VitaminD
3.3. Vitamin D
VitaminD3(1,25OHcholecalciferol;C27H44O;IDIUPAC:(3β,5Z,7E)-9,10-secocholesta-5,7,10
Vitamin D3 (1,25 OH cholecalciferol; C27H44O; ID IUPAC: (3β, 5Z, 7E)-9,10-secocholesta-5,7,10
(19)-trien-3-ol) (Figure 3) is a secosteroid hormone with a molar mass of 384.64 g/mol which
(19)-trien-3-ol) (Figure 3) is a secosteroid hormone with a molar mass of 384.64 g/mol which plays a
plays a fundamental role in mineral metabolism, but also in the regulation of immune response,
fundamental role in mineral metabolism, but also in the regulation of immune response, cell
celldifferentiationandinflammation,withimportantrepercussionsonbothliverandcardiovascular
differentiation and inflammation, with important repercussions on both liver and cardiovascular
health. Inthehumanbody,vitaminDisderivedforapproximately10%fromthediet,whilefrom90%
health. In the human body, vitamin D is derived for approximately 10% from the diet, while from
fromthecutaneousconversionof7-dehydrocholesteroltocolecalciferolforexposuretoultraviolet
90% from the cutaneous conversion of 7-dehydrocholesterol to colecalciferol for exposure to
B(UVB).Thenthecholecalciferolishydroxylatedfromtheliverbya25-hydroxylaseandthenfrom
ultraviolet B (UVB). Then the cholecalciferol is hydroxylated from the liver by a 25-hydroxylase and
the kidney from an alpha-1 hydroxylase, resulting in activation of 1,25-hydroxy-cholecalciferol or
then from the kidney from an alpha-1 hydroxylase, resulting in activation of 1,25-hydroxy-
calcitriol vitamin D. The decline in exposure to the sun linked to the modern lifestyle, associated
cholecalciferol or calcitriol vitamin D. The decline in exposure to the sun linked to the modern
withthereductioninageofthecapacityofhepaticandrenalhydroxylation,makealargepartofthe
lifestyle, associated with the reduction in age of the capacity of hepatic and renal hydroxylation, make
populationrelativelyandabsolutelydeficientinvitaminD[37].
a large part of the population relatively and absolutely deficient in vitamin D [37].

Figure 3. Chemical structure of Vitamin D3.
Figure3.ChemicalstructureofVitaminD3.
Vitamin D deficiency and non-alcoholic hepatosteatosis could be associated only for the high
VitaminDdeficiencyandnon-alcoholichepatosteatosiscouldbeassociatedonlyforthehigh
prevalence of both conditions in the general population. However, recent epidemiological evidence
prevalenceofbothconditionsinthegeneralpopulation. However,recentepidemiologicalevidence
shows that in patients with NAFLD they are more frequently deficient in vitamin D than in the
showsthatinpatientswithNAFLDtheyaremorefrequentlydeficientinvitaminDthaninthegeneral
general population, and the circulating vitamin D levels are proportional to the degree of fibrotic
population,andthecirculatingvitaminDlevelsareproportionaltothedegreeoffibroticevolutionof
evolution of NAFLD [38]. Nevertheless, not all the studies are in agreement: a recent metanalysis of
NAFLD[38]. Nevertheless,notallthestudiesareinagreement: arecentmetanalysisofobservational
observational studies involving 974 NAFLD patients, showed no difference in 25-hydroxyvitamin D
studiesinvolving974NAFLDpatients,showednodifferencein25-hydroxyvitaminDlevelsamong
levels among NAFLD patients with high NAFLD activity score (NAS) versus low NAS (MD = −0.93,
NAFLDpatientswithhighNAFLDactivityscore(NAS)versuslowNAS(MD=−0.93,95%CI−2.45
95% CI −2.45 to 0.58) and also high fibrosis score versus low fibrosis score (MD = 0.88, 95% CI −2.65
to 0.58) and also high fibrosis score versus low fibrosis score (MD = 0.88, 95% CI −2.65 to 4.42).
to 4.42). Despite evidence implicating vitamin D in NAFLD pathogenesis, serum 25-hydroxyvitamin
DespiteevidenceimplicatingvitaminDinNAFLDpathogenesis,serum25-hydroxyvitaminDmay
D may not be associated with NAFLD histologic severity [39]. In addition, in the study of Barchetta
notbeassociatedwithNAFLDhistologicseverity[39]. Inaddition, inthestudyofBarchettaetal.
et al. oral vitamin D supplementation (2000 IU/day) over 24 weeks did not improve hepatic steatosis
oralvitaminDsupplementation(2000IU/day)over24weeksdidnotimprovehepaticsteatosisor
or metabolic/cardiovascular parameters in diabetic patients with NAFLD [40]. In contrast, the study
metabolic/cardiovascularparametersindiabeticpatientswithNAFLD[40]. Incontrast,thestudyof
of Lim et al. suggests that serum 25-hydroxyvitamin D levels may be a risk factor for metabolic
Limetal. suggeststhatserum25-hydroxyvitaminDlevelsmaybeariskfactorformetabolicsyndrome
syndrome in patients with NAFLD [41].
inpatientswithNAFLD[41].
Table 3 summarizes the available evidence that binds vitamin D and NAFLD from a
Table 3 summarizes the available evidence that binds vitamin D and NAFLD from a
pathophysiological point of view, justifying vitamin D supplementation in patients affected by this
pathophysiological point of view, justifying vitamin D supplementation in patients affected by
condition [42,43]. Moreover, integration is justified by the virtual absence of side effects for non-
this condition [42,43]. Moreover, integration is justified by the virtual absence of side effects for
pharmacological dosages of supplementation, because vitamin D deficiency is almost pandemic, and
non-pharmacologicaldosagesofsupplementation,becausevitaminDdeficiencyisalmostpandemic,
for the positive actions that vitamin performs not only at the level of the bone and liver, but also on
andforthepositiveactionsthatvitaminperformsnotonlyattheleveloftheboneandliver,butalso
the immune and cardiovascular system [44,45].
ontheimmuneandcardiovascularsystem[44,45].
Nutrients2018,10,1153 7of18
Table3.PathophysiologicalMechanismsThatBindVitaminDandNAFLD.
ProposedMechanism SupportTests Ref.
• MicelackingvitaminDreceptorsareinsulin-resistant
• VitaminDmodulatesthetranscriptionoftheinsulingene
• VitaminDdeficiencyworsensthesecretoryresponseofbeta-cellsin
Insulin-sensitivityimprovement responsetocarbohydrateloading [46,47]
• VitaminDimprovesglucosetransportinmusclecells
• VitaminDupregulatesthetranslocationofGLUT4andtheuseofglucose
byadipocytes
• HigherlevelsoflivervitaminDareassociatedwithhigherlevelsof
adiponectin(inverselyproportionaltoadipocyticflogosis)
• Inanimalmodels,vitaminDsupplementationreducestheamountofIL-6
Reductionofinflammationof inadipocytes
[48–50]
adiposetissue • TreatmentofhumanadipocyteswithvitaminDinhibitsNF-kBandreduces
thereleaseofproinflammatorycytokines
• VitaminDinhibitsthechemotaxisofmacrophagesandincreasesthe
expressionofadiponectininpreadipocytes
• VitaminDdeficiencytriggersTollreceptorsandexacerbates
liverinflammation
Reductionofhepatic • Artificiallightinginratsreducesthedegreeofinflammationand
[51,52]
inflammation hepaticapoptosis
• TheexpressionofthevitaminDreceptoroncholangiocytesisinversely
proportionaltotheseverityofsteatosisandNAFLDscores
• VitaminDinhibitstheproliferationofhepaticstellatecellsinvitro
• VitaminDreducespro-fibroticmarkerlevels(asTIMP-1)andthe
Slowdownofliverfibrosis [53]
productionoftypeIcollagenincellculturesofhepaticstellatecells
• VitaminDreceptorknockoutmicespontaneouslydevelophepaticfibrosis
GLUT4=glucosetransportertype4, IL=Interleukin, NF-kB=nuclearfactorkappa-light-chain-enhancerof
activatedBcells,TIMP-1=tissueinhibitorsofmetalloproteinases-1.
SomeclinicalstudiesshowthatdailyvitaminDsupplementationimprovesinsulinresistance
and related parameters in patients with NAFLD [54,55]. Again, vitamin D supplementation can
alsohavepositiveimplicationsonthecardiovascularsystem. Infact,whileitsdeficiencyhasbeen
associated with a risk of hypertension and vascular ageing. Its supplementation, on the contrary,
wouldsignificantlyreducethelevelsofhighsensitivityCreactiveprotein,knownasanindependent
riskfactorforcardiovasculardiseases,asdemonstratedbythemeta-analysisof10studiesinvolving
924participants[56].
3.4. PolyunsaturatedFattyAcidsoftheOmega-3Series
Thepolyunsaturatedfattyacidsoftheseriesomega-3(Figure4)areessentialfattyacidsthatthe
Nhuutmrienatns 2b0o18d, y10i,s xu FnOaRb PlEeEtRo RsEyVnItEhWes izeandmusttakethemwiththediet. 8 of 20

FigFuirgeu 4r.e C4h.eCmhiecmali csatrluscttruurcetu orfe DoofcDooscaohseaxhaeexnaoeinc oaiccida c(iDdH(DAH) aAn)da neidcoesicaopseanpteanentaoeinc oaiccidac (iEdP(AEP).A ).
In the human organism, omega-3 fatty acids are involved in a very high number of biological
Inthehumanorganism,omega-3fattyacidsareinvolvedinaveryhighnumberofbiological
activities that make them fundamental for adequate development and for the maintenance of the
activitiesthatmakethemfundamentalforadequatedevelopmentandforthemaintenanceofthehealth
health status of different organs and tissues. Although a balanced diet can theoretically provide an
adequate amount of omega-3 fatty acids, the qualitative and biodiversity impoverishment of the
components of the diet, the methods of processing and cooking, and the increase in functional
demands of the organism makes supplementation with omega-3 fatty acids increasingly necessary
[57]. A recent meta-analysis of controlled clinical trials has shown that supplementation with
polyunsaturated fatty acids of the omega-3 series, mainly docosahexaenoic acid (DHA), and
eicosapentaenoic acid (EPA), contributes significantly to the reduction of circulating levels of AST
and gamma-glutamyl transferase [58]. This effect, associated with the known hypotriglyceridemic
and anti-inflammatory actions of omega-3 fatty acids, places them among the potentially active and
effective nutraceuticals in the management of NAFLD and NASH [59]. A meta-analysis of 4
randomized clinical trials conducted in 263 children showed that long-term supplementation with
EPA and DHA is associated with a 25% reduction of both circulating levels of AST and ALT, and the
degree of steatosis assessed by liver ultrasound scan, with no side effects [60].
3.5. Astaxanthin
A possible nutraceutical alternative to vitamin E (to be considered to avoid the problem of
balancing between hepatoprotective dose and cardio-injurious dose) is the use of astaxanthin
(C40H52O4: ID IUPAC: (6S)-6-Hydroxy-3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-[(4S)-4-hydroxy-
2,6,6-trimethyl-3-oxo-1-cyclohexenyl]-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-
2,4,4-trimethyl-1-cyclohex-2-enone), a carotenoid of marine origin of the colour purplish-red, very
stable, with an antioxidant activity in vitro extremely more powerful than the most common natural
antioxidants (e.g., vitamins A, E, and C, lycopene, resveratrol), with a molar mass of 596,841 g/mol
(Figure 5) [61]. In preclinical experimental models, astaxanthin is more effective than vitamin E in
reducing lipogenesis, insulin resistance, hepatic inflammation, and fibrogenesis, and therefore
appears to be the ideal natural antioxidant for the prevention of liver injury induced by NAFLD [62].
However, there is still no direct evidence on humans of these promising data.

Figure 5. Chemical structure of Astaxanthin.
Nutrients 2018, 10, x FOR PEER REVIEW 8 of 20

Figure 4. Chemical structure of Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
Nutrients2018,10,1153 8of18
In the human organism, omega-3 fatty acids are involved in a very high number of biological
activities that make them fundamental for adequate development and for the maintenance of the
shtaetaultsho sftdaitfufes roefn tdoifrfgearennsta onrdgatinsssu aensd. Atilstshuoeusg. hAaltbhaoluagnhce ad bdaileatnccaendt hdeieotr ectainca tlhlyeoprreotvicidalelya npraodveiqduea aten
aamdeoquunattoef aommoeugnat- 3offa totmyaegciad-s3, ftahtetyq uaacliidtas,t itvheea qnudabliitoadtiivvee rasnitdy ibmiopdoivveerrsisithym iemnptoovfethrieshcmomenpto nofe nthtse
ocfotmhepodnieetn,ttsh oefm theteh oddiest,o fthper omceesthsiondgs aonfd pcrooockeisnsgin,ga nadndth ecoionkcirnegas, eainndf uthnec tiinoncraeladsee mina nfdusncotfiotnhael
odregmanainsdms mofa tkhees osrugpapnliesmme mntaaktieosn suwpipthleommenegtaat-i3onfa wttyitha coimdseginac-3re faastitnyg alycidnse cienscsraeraysi[n5g7l]y. nAecreescseanrty
m[5e7t]a. -aAn arleycseisnto fmceotna-taronlalelydsicsl inofic aclontrtiraollslehda sclsihnoicwaln ttrhiaalts shuapsp lsehmowennt atthioant wsuipthplpeomlyenutnastaiotunr awteitdh
fpatotlyyuancisdastuorfattehde ofmatteyg aa-3cidsesr ioesf ,tmhea inolmyedgoac-o3s ashereixease, nmoiacinalcyid d(oDcHosAa)h,eaxnadeneoicico saacpiden t(aDeHnoAic), aacnidd
(eEiPcAos)a,pceonnttareibnuotiecs asciigdn (iEfiPcaAn)t,l ycotnotrthibeurteeds usicgtinoinficoafnctliyrc utola tthineg reledvuecltsioonf AofS cTiracnudlatgianmg mleva-eglslu otfa mASyTl
tarannds fgearmasmea[5-g8]lu. Ttahmisyel ftfreacnt,safesrsaoscei a[t5e8d].w Tihthis thefefekcnt,o awsnsohcyiapteodtr iwgliythce trhide ekmniocwann dhyanptoit-rinigfllyamcemridaetomryic
aacntido nasnotif-ionmflaemgam-3aftaotrtyy aaccitdiosn,sp loafc eosmthegema-3a mfatotnyg atchidesp, optleancteisa ltlhyeamct iavmeoanndg ethffee cptoivteenntuiatlrlayc eaucttiivcael sanind
tehfefemctaivnea gnemuternatceouftNicAalFsL iDn atnhde NmAaSnHag[5em9].enAt moef taN-aAnFalLyDsi saonfd4 rNanAdSoHm i[z5e9d].c lAin icmalettrai-aalnsacloynsdisu cotfe d4
irna2n6d3ocmhiizldedre nclisnhiocwale tdritahlsa tcloonndgu-tcetremd isnu p2p63le cmheilndtraetino nshwowithedE PtAhaat nlodnDg-HteArmis sausspopclieamteednwtaittihona w25i%th
rEePdAuc atinodn DoHf bAo tihs acsisrocucilaatteindg wleitvhe als 2o5f%A rSeTduacntidonA oLfT b,oatnhd citrhceuldaetginrge eleovfeslst eoaft oAsSisT aasnsde sAseLdT,b aynldiv tehre
udletrgarseoeu onfd stsecaatno,swis iathssneossseidd ebyef lfievcetsr u[6l0tr]a.sound scan, with no side effects [60].
3.5. Astaxanthin
3.5. Astaxanthin
ApossiblenutraceuticalalternativetovitaminE(tobeconsideredtoavoidtheproblemofbalancing
A possible nutraceutical alternative to vitamin E (to be considered to avoid the problem of
betweenhepatoprotectivedoseandcardio-injuriousdose)istheuseofastaxanthin(C40H52O4:IDIUPAC:
balancing between hepatoprotective dose and cardio-injurious dose) is the use of astaxanthin
(6S)-6-Hydroxy-3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1-cyclohexenyl]
(C40H52O4: ID IUPAC: (6S)-6-Hydroxy-3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-[(4S)-4-hydroxy-
-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-2,4,4-trimethyl-1-cyclohex-2-enone),
2,6,6-trimethyl-3-oxo-1-cyclohexenyl]-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-
a carotenoid of marine origin of the colour purplish-red, very stable, with an antioxidant activity
2,4,4-trimethyl-1-cyclohex-2-enone), a carotenoid of marine origin of the colour purplish-red, very
invitroextremelymorepowerfulthanthemostcommonnaturalantioxidants(e.g.,vitaminsA,E,
stable, with an antioxidant activity in vitro extremely more powerful than the most common natural
and C, lycopene, resveratrol), with a molar mass of 596,841 g/mol (Figure 5) [61]. In preclinical
antioxidants (e.g., vitamins A, E, and C, lycopene, resveratrol), with a molar mass of 596,841 g/mol
experimentalmodels,astaxanthinismoreeffectivethanvitaminEinreducinglipogenesis,insulin
(Figure 5) [61]. In preclinical experimental models, astaxanthin is more effective than vitamin E in
resistance, hepatic inflammation, and fibrogenesis, and therefore appears to be the ideal natural
reducing lipogenesis, insulin resistance, hepatic inflammation, and fibrogenesis, and therefore
antioxidantforthepreventionofliverinjuryinducedbyNAFLD[62]. However,thereisstillnodirect
appears to be the ideal natural antioxidant for the prevention of liver injury induced by NAFLD [62].
evidenceonhumansofthesepromisingdata.
However, there is still no direct evidence on humans of these promising data.

Figure 5. Chemical structure of Astaxanthin.
Figure5.ChemicalstructureofAstaxanthin.

3.6. CoenzymeQ10
Another antioxidant of recent interest for the management of NAFLD is Coenzyme Q10
(Ubidecarenone; C59H90O4; ID IUPAC: 2-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E)-3.7,
11,15,19,23,27,31,35,39-Decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-
methylcyclohexa-2,5-diene-1,4-dione),moleculeofmolarmass863.34g/mol,particularlyconcentrated
inheart,striatedmuscleandliver,butpresentinallcellsoftheorganism(Figure6)[63].
In a recent double-blind randomized placebo clinical study, 100 mg/day of Coenzyme Q10
for3weeksresultedinasignificantreductionoftransaminases,gamma-GT,hsCRPanddegreesof
NAFLD, as well as improvement of the adiponectin/leptin ratio [64]. In addition, coenzyme Q10
couldhelptoimprovethelipidpatterntypicallyassociatedwithNAFLD[65],aswellasreducing
oxidizedLDLlevelsandarterialpressure. ThemainlimitationoftheuseofcoenzymeQ10istheneed
for high dosages (>100 mg/day) of pharmaceutically modified formulations to have an increased
Nutrients 2018, 10, x FOR PEER REVIEW 9 of 20
3.6. Coenzyme Q10
Another antioxidant of recent interest for the management of NAFLD is Coenzyme Q10
(Ubidecarenone; C59H90O4; ID IUPAC: 2-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E)-3.7 ,
11,15,19,23,27,31,35,39-Decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-
methylcyclohexa-2,5-diene-1,4-dione), molecule of molar mass 863.34 g/mol, particularly
concentrated in heart, striated muscle and liver, but present in all cells of the organism (Figure 6) [63].
Nutrients 2018, 10, x FOR PEER REVIEW 9 of 20
3.6. Coenzyme Q10
Another antioxidant of recent interest for the management of NAFLD is Coenzyme Q10
N(Uutbriiednetsc2a0r1e8n,1o0n,1e1; 53C59H90O4; ID IUPAC: 2-[(2E, 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E)-93o.7f 18,
11,15,19,23,27,31,35,39-Decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-
bmioetahvyaliclaybcilloihtye,xsain-2c,e5-cdoieennzey-1m,4e-dQio10neb)y, itmseolflehcauslep ooorf ormalobliaora vamilaasbsi lit8y.63O. 3n4t hego/mthoelr, hapnadrt,iictuhlaarslya
concentrated in heart, striated muscle and liver, but present in all cells of the organism (Figure 6) [63].
veryhighsafetyprofilewithoutFaingyurrei s6k. Cohfedmruicgali nsttreurcatcutrieo nofs c[o6e6n]z.yme Q10.
In a recent double-blind randomized placebo clinical study, 100 mg/day of Coenzyme Q10 for 3
weeks resulted in a significant reduction of transaminases, gamma-GT, hsCRP and degrees of
NAFLD, as well as improvement of the adiponectin/leptin ratio [64]. In addition, coenzyme Q10
could help to improve the lipid pattern typically associated with NAFLD [65], as well as reducing
oxidized LDL levels and arterial pressure. The main limitation of the use of coenzyme Q10 is the need
for high dosages (>100 mg/day) of pharmaceutically modified formulations to have an increased
bioavailability, since coenzyme Q10 by itself has poor oral bioavailability. On the other hand, it has a

very high safety profile without any risk of drug interactions [66].
FFiigguurree 66.. CChheemmiiccaall ssttrruuccttuurree ooff ccooeennzzyymmee QQ1100..
3.7. Berberine
3.7. BIenr bae rrienceent double-blind randomized placebo clinical study, 100 mg/day of Coenzyme Q10 for 3
weeks rBeesrublteerdin ein h yad sriogcnhilfoicraidnet irse dau qcutiaotne rnofa rtyr aanmsammoinniausmes , saglat mbmeloan-GgTin, gh tsoC tRhPe ganrodu pd eogfr eaelks aolofi ds
Berberine hydrochloride is a quaternary ammonium salt belonging to the group of alkaloids
NAbFeLnDzy, laisso wqueilnl oalsin iem (pCro20vHem18eNntO o4f +th) eo af dai pmonoelacrti nm/laespst in33 r6a.3ti6o1 2[6 4g]/.m Ionl a(dFdigituioren , 7c)o, eenxztryamctee dQ 1fr0o m
benzylisoquinoline (C20H18NO4 +) of a molar mass 336.3612 g/mol (Figure 7), extracted from
counldum heerlpo utso mimepdriocivnea lt hpel alinptisd (pina ttpearrnt itcyuplaicra tllhyo saes soofc iathteed B weribther iNs AgeFnLuDs )[ 6a5n]d, a es nwdeolwl aesd rwediuthc inligp id-
numerousmedicinalplants(inparticularthoseoftheBerberisgenus)andendowedwithlipid-lowering
oxildoiwzeedr iLnDg Lan ledv ienlssu alnind- saerntesriitaizl ipnrge sascutiroen. Ts hclee maralyin d leimmiotnatsitornat oefd t hine huusem oafn cso [e6n7z]y. me Q10 is the need
andinsulin-sensitizingactionsclearlydemonstratedinhumans[67].
for high dosages (>100 mg/day) of pharmaceutically modified formulations to have an increased
bioavailability, since coenzyme Q10 by itself has poor oral bioavailability. On the other hand, it has a
very high safety profile without any risk of drug interactions [66].
3.7. Berberine
Berberine hydrochloride is a quaternary ammonium salt belonging to the group of alkaloids
benzylisoquinoline (C20H18NO4 +) of a molar mass 336.3612 g/mol (Figure 7), extracted from
numerous medicinal plants (in particular those of the Berberis genus) and endowed with lipid-
lowering and insulin-sensitizing actions clearly demonstrated in humans [67].

FiguFirgeu7r.eC 7h. eCmhiecmalicsatrlu scttruurcetuorfeb oefr bbeerribneer.ine.
Some preliminary clinical reports confirmed that these actions of berberine are also related to
Somepreliminaryclinicalreportsconfirmedthattheseactionsofberberinearealsorelatedto
the improvement of levels of indirect markers of hepatosteatosis (Hepatic Steatosis Index, Lipid
the improvement of levels of indirect markers of hepatosteatosis (Hepatic Steatosis Index, Lipid
Accumulation Product) for short-term supplements (2–4 months) at doses of 500 mg/day [68]. These
Accumulation Product) for short-term supplements (2–4 months) at doses of 500 mg/day [68].
data were recently collected in a meta-analysis of six randomized clinical trials that evaluated 501
Thesedatawererecentlycollectedinameta-analysisofsixrandomizedclinicaltrialsthatevaluated
patients, confirming the positive effect of berberine on lipid parameters, insulin resistance, hepatic
501 patients, confirming the positive effect of berberine on lipid parameters, insulin resistance,
markers and degree of hepatic steatosis in patients with NAFLD. However, these studies have used
hepatic markers and degree of hepatic steatosis in patients with NAFLD. However, these studies
relatively high doses (1000–1500 mg/day), which may be associated with intestinal disorders [69].
have used relatively high doses (1000–1500 mg/day), which may be associated w ith intestinal
Even berberine has a poor oral bioavailability that can, however, be improved by ad hoc
disorders [69]. Even berberineFhigausrea 7p. oCohremoricaall bstirouacvtuariela obfi blietrybethriante.c an, however, be improved by
pharmaceutical techniques.
adhocpharmaceuticaltechniques.
Some preliminary clinical reports confirmed that these actions of berberine are also related to
3th.8e. Cimuprcruomveinment of levels of indirect markers of hepatosteatosis (Hepatic Steatosis Index, Lipid
Accumulation Product) for short-term supplements (2–4 months) at doses of 500 mg/day [68]. These
Curcumin(C21H20O6,IDIUPAC:(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,
data were recently collected in a meta-analysis of six randomized clinical trials that evaluated 501
5-dione,molarmass: 368.38g/mol)(Figure8),anotherknowninsulin-sensitizingagentextractedfrom
patients, confirming the positive effect of berberine on lipid parameters, insulin resistance, hepatic
Curcumalonga,hasbeenassociatedinnumerouspreclinicalstudiesandinrecentpreliminaryclinical
markers and degree of hepatic steatosis in patients with NAFLD. However, these studies have used
trialswithasignificantimprovementinNAFLD-relatedparameters[70]. Inparticular,aclinicalstudy
relatively high doses (1000–1500 mg/day), which may be associated with intestinal disorders [69].
of100Asianpatientswithmetabolicsyndromehasshownastatisticallysignificantimprovementin
Even berberine has a poor oral bioavailability that can, however, be improved by ad hoc
thedegreeofhepaticsteatosisassessedbyliverultrasoundwithadailyadministrationof400mgof
pharmaceutical techniques.
curcumin[71]. Inanothercontrolledclinicalstudyconductedon102Iranianpatients,supplementation
withphytosomalcurcumin,500mgb.i.d. for8weeksledtoasignificantreductionintransaminase
levels,waistcircumference,bodymassindex,butespeciallythedegreeofhepaticsteatosisin75%
of the treated subjects. Although these data are particularly promising, it should be noted that
Nutrients 2018, 10, x FOR PEER REVIEW 10 of 20
Nutrients 2018, 10, x FOR PEER REVIEW 10 of 20
3.8. Curcumin
3.8. Curcumin
Curcumin (C21H20O6, ID IUPAC: (1E, 6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-
Curcumin (C21H20O6, ID IUPAC: (1E, 6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-
heptadiene-3,5-dione, molar mass: 368.38 g/mol) (Figure 8), another known insulin-sensitizing agent
heptadiene-3,5-dione, molar mass: 368.38 g/mol) (Figure 8), another known insulin-sensitizing agent
extracted from Curcuma longa, has been associated in numerous preclinical studies and in recent
extracted from Curcuma longa, has been associated in numerous preclinical studies and in recent
preliminary clinical trials with a significant improvement in NAFLD-related parameters [70]. In
preliminary clinical trials with a significant improvement in NAFLD-related parameters [70]. In
particular, a clinical study of 100 Asian patients with metabolic syndrome has shown a statistically
particular, a clinical study of 100 Asian patients with metabolic syndrome has shown a statistically
significant improvement in the degree of hepatic steatosis assessed by liver ultrasound with a daily
significant improvement in the degree of hepatic steatosis assessed by liver ultrasound with a daily
administration of 400 mg of curcumin [71]. In another controlled clinical study conducted on 102
administration of 400 mg of curcumin [71]. In another controlled clinical study conducted on 102
Iranian patients, supplementation with phytosomal curcumin, 500 mg b.i.d. for 8 weeks led to a
Iranian patients, supplementation with phytosomal curcumin, 500 mg b.i.d. for 8 weeks led to a
significant reduction in transaminase levels, waist circumference, body mass index, but especially the
significant reduction in transaminase levels, waist circumference, body mass index, but especially the
degree of hepatic steatosis in 75% of the treated subjects. Although these data are particularly
degree of hepatic steatosis in 75% of the treated subjects. Although these data are particularly
Nutrients2018,10,1153 10of18
promising, it should be noted that the positive effects are often observed for high supplementations
promising, it should be noted that the positive effects are often observed for high supplementations
(usually >1500 mg/day) of pure curcumin, with consequent problems of treatment compliance and
(usually >1500 mg/day) of pure curcumin, with consequent problems of treatment compliance and
ctchooessttpss o((ppsiaatrrivttiieaallellyyff emmctiitstiiggaaaretteeoddf twweniitthho btthhseeer uuvsseeed oofffo nrneehwwig,, h mmsoourrpeep bbliieoomaavveaaniitllaaatbbiolleen ppshh(uaarrsmmuaaalcclyeeuu>tti1icc5aa0ll 0 ffoomrrmmg/uudllaaattyiioo)nnossf)) p[[77u22r]]e..
TcTuhhriicssu iisms bbineecc,aawuuisstehe cccuuorrnccsuuemmquiinnen aatllsspoor ohhbaalsse maa ppsooooofrrt rooerraaatllm bbeiioonaatvvcaaoiimllaapbbliiillaiittnyyc,, e tthhaaanttd cccaaonns,, thhsoo(wpwaeervvtieearrl,,l ybbeem iimmitippgrarootevvdeeddw bbityyh ““taahdde
huhosoecc””o fppnhheaawrrmm,maaccoeeruuettiibcciaaolla ttveeaccihhlannbiiqqleuupeessh..a rmaceuticalformulations)[72]. Thisisbecausecurcuminalsohasa
poororalbioavailability,thatcan,however,beimprovedby“adhoc”pharmaceuticaltechniques.
FFiigguurree 88.. CChheemmiiccaall ssttrruuccttuurree ooff ccuurrccuummiinn..
Figure 8. Chemical structure of curcumin.
33..99.. RReessvveerraattrrooll
3.9. Resveratrol
RReessvveerraattrrooll ((33,,55,,44′-(cid:48)-ttrrihihyyddrrooxxyy-t-rtraannss-s-stitliblbeennee, ,CC141H4H121O2O3,3 m, omlaorl amr amssa: s2s:28.22258 .g2/5mogl/) miso la) nisona-
Resveratrol (3,5,4′-trihydroxy-trans-stilbene, C14H12O3, molar mass: 228.25 g/mol) is a non-
nfloavno-flnaovido npohiednpolh (eFnioglu(rFei 9g)u prear9t)icpualarrtliycu cloanrlcyenctornacteedn tirna ttehde ignratphee sgkrianp peesekl,i nbupte aells,ob iunt tahles oexitnratchtes
flavonoid phenol (Figure 9) particularly concentrated in the grape skin peel, but also in the extracts
eoxf tPraoclytsgoonfuPmol ycugosnpiudmatucums,p pidoaoturmly, oproaollryly boioraalvlyaiblaiobalev a(iifl anbolte c(hifenmoitccahlleym micoadlliyfimedo)d, cifiheadra),cctehrairzaecdte bryiz eadn
of Polygonum cuspidatum, poorly orally bioavailable (if not chemically modified), characterized by an
bimypaonrtiamnpt oarnttainoxtiadnatniot,x vidaasonpt,rvoatescotpivreo t(ebcottivhe ce(breobthracl earnedb rpaelrainpdhepraelr)i pahnedr ainl)sualnind-isnesnusiltiniz-isnegn saicttiizvinitgy
important antioxidant, vasoprotective (both cerebral and peripheral) and insulin-sensitizing activity
a[7c3ti,v74it]y. P[7r3el,7im4]i.naPrrye lcimlininicaarly dcaltian iacpalpedaart atoa pcopneatrradtoicct opnrtercaldinicictapl rleitcelirnaitcuarle,l isteurgagtuesrtei,nsgu ag gpeostteinngtiaal
[73,74]. Preliminary clinical data appear to contradict preclinical literature, suggesting a potential
pefoftiecnactiya loeff firceasvcyeroaftrroesl vienr aimtroplrionviimngp rNovAinFgLDN-AreFlaLtDed-r eplaatreadmpeaterarsm [e7t5e]r.s H[7o5w].eHvoewr, etvheers,et hsetsuedsiteusd aieres
efficacy of resveratrol in improving NAFLD-related parameters [75]. However, these studies are
aurseuuaslluya sllhyosrht o(troto(t oshoosrhto trot htoavhea vaena inmipmapcat cotno tnhteh leivlievre srtsrturcutcuturer)e )anandd aarere ccoonndduucctteedd wwiitthh rreessvveerraattrrooll
usually short (too short to have an impact on the liver structure) and are conducted with resveratrol
ddoosseess iinnccoommppaattiibbllee wwiitthh tthhee iinnssuulliinn--sseennssiittiizziinngg aaccttiioonn tthhaatt ccoouulldd iimmpprroovvee NNAAFFLLDD.. IInn ffaacctt,, wwhheenn uusseedd
doses incompatible with the insulin-sensitizing action that could improve NAFLD. In fact, when used
aatt tthhee aapppprroopprriiaattee ddoossee aanndd ffoorr lloonngg ppeerriiooddss,, rreessvveerraattrrooll hhaass aallrreeaaddyy sshhoowwnn ttoo eexxeerrtt aann iimmppoorrttaanntt
at the appropriate dose and for long periods, resveratrol has already shown to exert an important
aannttiihhyyppeerrtteennssiivvee eeffffeecctt iinn tthhoossee aaffffeecctteedd bbyy NNAAFFLLDD [[7766]]..
antihypertensive effect in those affected by NAFLD [76].

FFFiiiggguuurrreee 999... CCChhheeemmmiiicccaaalll ssstttrrruuuccctttuuurrreee ooofff rrreeesssvvveeerrraaatttrrrooolll...
3.10. Salvia Miltiorrhiza
33..1100.. SSaallvviiaa MMiillttiioorrrrhhiizzaa
A meta-analysis of 8 controlled clinical trials that included 800 Asian patients showed how Salvia
AA mmeettaa--aannaallyyssiiss ooff 88 ccoonnttrroolllleedd cclliinniiccaall ttrriiaallss tthhaatt iinncclluuddeedd 880000 AAssiiaann ppaattiieennttss sshhoowweedd hhooww SSaallvviiaa
miltiorrhiza dry extract supplementation (red or Chinese sage, Danshen) leads to a significant
mmiillttiioorrrrhhiizzaa ddryrye xetxratrcatcstu psupplepmleemnteantitoantio(rne d(roerdC hoirn eCsheisnaegsee, Dsaagnes,h eDna)nlesahdesn)t olaeasdigsn itfioc aan tsirgendiuficctaionnt
reduction in plasma levels of transaminases associated with an increase in computerized
rinedpulacstimona leinv elpsloafsmtraan slaemveilnsa soefs atsrsaoncsiaamteidnwasietsh aanssioncciraetaesde inwcitohm paunt eirnizceredatsoem iong racpomhipcucotenrtirzaesdt
tomographic contrast between liver and spleen, indicative of a reduction in the degree of
tboemtwoegernaplihviecr aconndtrsapslte ebne,tiwndeiecna tilviveeorf aanredd uscptlieoenn,i nitnhdeicdaetgivree eooff hae praetdousctetiaotno siisn[ 7t7h]e. Ddeesgprietee thoef
interestintheseevidences,clinicaldataonCaucasiansubjectsarecurrentlylacking.
3.11. Probiotics
Growingliteratureshowsthatevenchronicsupplementationwithprobioticsand/orsymbiotics
couldimproveseveralparametersrelatedtoNAFLD(insulinresistance,plasmalevelsoftransaminases,
degree of lipid infiltration of the liver), but the available studies have all been conducted with
differentprobioticstrainsorassociationsanditisthereforedifficulttoprovideaspecificindicationfor
supplementation[78]. Undoubtedly,ifprobioticsaretobetakenforotherindications,theeffectonthe
possiblyco-hostedNAFLDcouldonlybepositive[79].
Promising results may come from certain probiotic strains. Preliminary RCTs have shown
that treatment with L. bulgaris or S. thermophilus reduces the levels of alanine aminotransferase,