Mauriac syndrome still exists

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Endocrinol Nutr. 2013;60(5):245–248

ENDOCRINOLOGÍA

Y

NUTRICIÓN

www.elsevier.es/endo

ORIGINAL

ARTICLE

Mauriac

syndrome

still

exists

Joana

Dias

∗

_,

_Soﬁa

_Martins,

_Susana

_Carvalho,

_Olinda

_Marques,

_Ana

_Antunes

ConsultadeEndocrinologiaPediatrica,ServiciodePediatria,HospitaldeBraga,Braga,Portugal

Received6September2012;accepted17December2012

KEYWORDS

Mauriacsyndrome; Diabetesmellitus; Adolescence

Abstract

Background/objective:Mauriacsyndrome(MS)isararecomplicationoftype1diabetesmellitus (DM1).Itisrelatedtolowinsulinconcentrationsandislesscommonsincelonger-actinginsulins became available.Itis characterized by hepatomegaly,growth andpuberty delay,and the presenceofelevatedtransaminasesandserumlipids.Theaimofthisstudywastodescribethe patientsfromapediatricdiabeticpopulationthatfulﬁllthecriteriaofMS.

Materialsandmethods: Aretrospectiveanalysisofthepediatricdiabeticpopulationwith diag-nosticcriteriaofMScurrentlyfollowedatHospitaldeBraga,wasperformed.

Results: Fromapopulationof91patientswithDM118years,6patientswiththecriteriaforMS wereidentiﬁed:5girls,and1boy.Theageatpresentationwas13---17years,withaminimum interval betweenDM1diagnosis andMScriteriaof4years.Allthepatientswereprescribed intensiveinsulintherapy(mediandailyinsulindose:0.88U/kg).Allhadaprevioushistoryof poorglycemiccontrolbeforethediagnosisofMSwithglycatedhemoglobin(HbA1c)between 8.8 and12.9%.Increase ofhepaticenzymeswas presentinall thepatients;4ofthem had associatedhepatomegaly.Allthegirlspresentedpubertydelayandcushingoidfeatures.None ofthepatientspresentedshortstatureand5ofthempresentedmixeddyslipidemia.

Conclusions: AlthoughMSisananciententitydescribedinDM1,itstillexists,particularlyin adolescentfemales. BeingawareofMS isofextremeimportancesince mostofthe clinical featuresarereversiblewithbetterglycemiccontrol.

PALABRASCLAVE

SíndromedeMauriac; Diabetesmellitus; Adolescencia

ElsíndromedeMauriactodavíaexiste

Resumen

Introducción/objetivo: ElsíndromedeMauriac(SM) esunacomplicaciónraradeladiabetes mellitusdetipo1(DM1),relacionadaconbajasconcentracionesdeinsulina,yesmenoscomún desdequeestándisponiblesinsulinasdelargaduracióndeacción.Secaracterizaporla hep-atomegalia,elretrasodelcrecimientoydelapubertadylaelevacióndelastransaminasasyde loslípidosséricos.Elobjetivodeesteestudiofueladescripcióndelospacientesconcriterios deSMenunapoblaciónpediátricaconDM1.

∗_{Corresponding}_author.

E-mailaddress:[email protected](J.Dias).

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246 J. Dias et al.

Materialymétodos: Análisisretrospectivodeunapoblaciónpediátricadiabéticaatendidaen elHospitaldeBragaconcriteriosdiagnósticosdeSM.

Resultados: Deunapoblaciónde91pacientesconDM1menoresde18añosfueronidentificados 6pacientesconcriteriosdeSM:5mujeresyunvarón.Laedaddepresentaciónfuede13a17 añosconunintervalomínimoentreeldiagnósticodeDM1ySMde4años.Todoslospacientes teníanprescritaunaterapiainsulínicaintensiva(dosismediadiaria:0,88U/kg).Todostenían unahistoriaprevia de malcontrolglucémicoantes deldiagnóstico deSM con hemoglobina glucosilada(HbA1c)entre8,8y12,9%.Lasenzimashepáticasestabanaumentadasentodoslos pacientesy4presentabanunahepatomegaliaasociada.Todaslasniñasmostrabanretrasode lapubertadyunaspectocushingoide.Ningúnpacienteteniatallabajay5teníandislipidemia mixta.

Conclusiones:AunqueelSMesunaentidadpocodescritaactualmente,aúnexiste, especial-menteenadolescentesfemeninas.IdentiﬁcarelSMesmuyimportanteyaquelamayoríade lasalteracionesclínicassonreversiblesconmejorcontrolglucémico.

Introduction

Mauriac syndrome (MS) is a rare complication of type 1 diabetes mellitus (DM1), characterized by hepatomegaly (hepatic glycogenosis), puberty and growth delay, dys-lipidemia, transaminase elevation and reduction of IGF1 (insulin-likegrowthfactor1).1_Cushingoid_features_may_also

bepresent.2

Theremaybedifferentformsandetiologiesinvolvedin Mauriac syndrome. However, there are common features noted in these patients and with adequate insulin treat-mentthereisreversalofgrowthfailureandhepatomegaly ifpresent.3

MS is more common in children and adolescents with poor glycemic control and increased susceptibility of complications,1_and_is_the_commonest_cause_of_hepatic

dys-functioninchildrenandadolescentswithDM1.4

Althoughitsrealincidenceisnotwell-known,duetothe reducednumberofreportedcasesintheliterature,equal incidenceisreportedinmalesandfemales,withmostofthe casesoccurringinadolescentsandyoungadults.2,5

Theauthorspresentaretrospectiveanalysisofpatients presentingdiagnosticcriteriaofMSfromthetype1diabetic populationfollowedcurrentlybypediatricendocrinologyin Braga’sHospital.

Materials

and

methods

CaseswereidentifiedbysearchingthePediatric endocrinol-ogyDM1 database for confirmed clinical and biochemical featuresofMSinpatientsunder18yearsatpresentation.A retrospectiveanalysiswasundertaken.Areviewofrecords wasconductedtodeterminepatients’ageatpresentationof DM1andMS,aswellasglycatedhemoglobin(HbA1c)value, hepaticenzymes,lipidprofileandmediandailyinsulindose atMS presentationand follow-updataafter MSdiagnosis. Dataregardingother complications of DM1(microvascular complications, specifically, retinopathy and nephropathy; macrovascularcomplications andneuropathies) were also collected.Data research endedin October 30, 2011. The study was approved by the Braga’s Hospital pediatric

endocrinology coordinator and an informed consent was signedbyparentsorchildrenlegalguardians.

Results

Froma population of91 pediatric patientswithDM1 (fol-lowedfromJanuary2005toOctober2011),weidentiﬁed6 patientswithdiagnosticcriteriaforMS:5girlsand1boy.

RegardingthesixpatientswithMS,themedianageatDM1 diagnosiswas7.8years(3---11years)andatMSpresentation 15.3years(13---17years).ThemedianintervalbetweenDM1 andMSdiagnosiswas7.5years(range4---14years).Allthe patientswereunderintensiveinsulintherapywithamedian dailyinsulindoseof0.88U/kg.

All had a previous history of poor glycemic control prior to the MS diagnosis with a median (glycosylated hemoglobin) HbA1c concentration at diagnosis of 12.3% (range 10.5---13.5%). The median HbA1c of the DM1 pop-ulation was 8.1% (normal HbA1c<6.5%). Non-compliance regardingnutritionalandinsulintherapyandself-monitoring wasacommonfeatureofallidentiﬁedMScases.

At presentation, the 5 girls presented cushingoid features, puberty dysfunction (primary amenorrhea in 2 patients and secondary amenorrhea in 3) and mixed dyslipidemia(high total cholesterol,low HDL[highdensity lipoprotein]cholesterolandhightriglycerides:cut-off val-uesof>200mg/dl fortotalcholesterol,<40mg/dlforHDL and >180mg/dl for triglycerides). The male patient pre-sentedpubertydelayanddyslipidemia.

Ofthe6patients,5presentedhepatomegaly(4conﬁrmed by abdominal ultrasound), and all showed transaminase elevation: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 3---22-fold above the upper normal limit. Liver function tests such as alkaline phos-phatase, prothrombin/partial prothrombin time and total bilirubinwerenormal,aswellasthyroidfunction,IgAand transglutaminase or anti-endomysium levels. None of the patientspresentedcriteriaofshortstature(allwerewithin thepercentilesP10---P75ofexpectedheightforageandsex, accordingtoCDC2010GrowthCharts).

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Mauriac syndrome still exists 247 T able 1 Clinical and biochemical features of patients with Mauriac syndrome at diagnosis. Sex DID (U/kg) HbA1c (%) Hepatomegaly Cushingoid features Puberty delay AL T (U/L) AST (U/L) Total/HDL cholesterol (mg/dl) Triglycerides (mg/dl) Male 0.76 12.9 5 cm No Yes 64 73 220/55 190 Female 0.97 12.4 19 cm Yes P rimary amenorrhea 431 235 320/33 360 Female 0.36 a 10.5 17 cm Yes P rimary amenorrhea 64 78 326/36 428 Female 1.72 13.5 No Yes Secondary amenorrhea 106 121 256/41 227 Female 0.76 13.0 21 cm Yes Secondary amenorrhea 115 282 310/40 277 Female 0.77 11.6 20 cm Yes P rimary amenorrhea 684 237 302/29 449 DID, daily insulin dose; HbA1c, glycated hemoglobin; AL T, alanine aminotransferase; AST , aspartate aminotransferase; HDL, high-density lipoprotein. a This adolescent was prescribed 1.2 U/kg, but receiving an actual dose of 0.36 U/kg (non-compliance).

After diagnosis, a stronger multidisciplinary approach (involving endocrinology, pediatrics, nutrition, psychology andpsychiatry)wasattemptedinordertoimproveglycemic control. The mean duration of follow-up was 1.8 years (1---3.5years).

Abettercontrolwasachievedin2girls,withareduction of HbA1ctoconcentrationsbelow9%andanimprovement regardingpubertyimpairment(normalizationofsecondary amenorrhea).Normalizationoftransaminaseconcentrations wasachievedonlyinone.Athirdpatientpresentedtransient improvedcontrolwithnormalizationofmensesand transam-inases.Inanotherpatient,anormalizationoftransaminase concentrations was observed with a modest decrease of HbA1c concentration (from 14.5% to 13%). Normalization oftransaminaseconcentrationsoccurredbetween4and12 weeks (median 9 weeks) after MS diagnosis. In the sixth patientnobetter glycemiccontrolwasachieved.None of thepatientsshowedanimprovementoflipidproﬁle.

The 6 patients had regular ophthalmologic evaluations andnoneshowedsignsofdiabeticretinopathy.Threeofthe 6presentedwithmicroalbuminuria(>30mg/dlin24h).

Discussion

Adolescence is a critical period of development charac-terized by changes in interpersonal roles, responsibilities andidentityconstruction.Thisperiodis morecomplexfor adolescents diagnosed with type 1 diabetes: in addition toexperiencing thesamechallenges astheirpeers,these adolescents must deal with intensive medical regimens, regularclinicappointments,carbohydratecalculationsand frequentdailymonitoringofbloodglucoselevels.Although newinsulinsandcarbohydratecountingapproachare cur-rentlyavailabletofacilitatemoreoptimalglycemiccontrol, manyadolescentswithtype1diabetesachievesuboptimal glycemiccontrolandinsomecaseswecanstillﬁndMS.

The features of MS are mostly related with deﬁcient insulinization. Patientscan develop hepatomegaly due to intrahepaticglycogendeposition;ifthesepatientsalsohave elevated liverenzymes, dyslipidemia,cushingoid features anddelayedgrowthorsexualmaturation,Mauriacsyndrome can be diagnosed.4 _The _literature _documents _decreased

blood glucose monitoring frequency and deterioration in blood glucose control and HbA1c, with few adolescents achievingoptimalHbA1cvalues(<7.5%).6_Although_being_an

adolescent greater risk, MS can occur in any age if good metaboliccontrolisnotachieved.2

In poorly controlled DM1 patients, the hyperglycemic periodsfollowed byoccasionalhyperinsulinizationandthe highcortisollevelsashypoglycemiacontra-regulatory hor-mone leadto hepatic glycogen storage. In hyperglycemic situations, glucose goesfreely into the hepatocyteand is also storedas glycogen.On theother hand,the deﬁcient insulinizationduetopoorglycemiccontrolleadsto lipoly-sisandketoneliberation.Ketosisactivatescortisolsynthesis promotingthereleaseoffattyacidsandhyperglycemia.7,8_A

commonﬁndinginthesepatientsisthegrowthdelayand/or hypogonadismsecondarytothehighcortisollevels.4

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248 J. Dias et al.

timeofdiagnosis,meaningthattheyhadalreadyachieveda normalstaturebeforethedetiorationofmetaboliccontrol. The other reason is that data of parents’ height wasnot availableinordertoevaluatetheexpectedgeneticheight, sothatsomemightbeinanormalpercentileforsexandage butbelowtheirgeneticpotential.

Asinotherseriesofcasesrecentlydescribed,alsowith asmallnumberofpatients, theincidenceofMS seemsto begreater in adolescent girls. The poor glycemic control priorto the diagnosis and the elevated daily insulin dose arealsodescribedinotherseries.4,9_These_data_suggest_the

importanceofhigh vigilancein promotingpatient compli-ancetoinsulindosingratherthansimplyincreasinginsulin dosageinresponsetohyperglycemiawithsubsequentweight gain.

Withadequate insulin treatment thereis a reversal of thosefeatures;however, overlyaggressiveinsulindelivery couldresultinrapid deteriorationof diabeticretinopathy andnephropathy.3_The _reduction_of_hepatic_enzymes_after

achieving reasonable glycemic control suggests that liver biopsyandotherextensivework-upmaybeunnecessaryin themanagementofsimilarpatients.9

Theauthorspresentthisseriestostresstheimportance of high index of suspicion of MS in diabetic adolescents withhepatomegaly, transaminaseelevation, dyslipidemia, growthorsexualdelay andcushingoid features.Aprompt diagnosisandamultidisciplinaryapproacharethebasisof thetreatment,butpreventionisdesirable.Goodmetabolic control allows improving liver function tests as well as a reduction of the probability of developing other dia-betic complications related to persistent hyperglycemia. As this series shows, adolescents and especially females are more vulnerable to this disease and, due to their bio-psycho-socialproﬁle, therapeuticadhesion isnot easy

to achieve, despite new insulin treatments and dietary approach.

Conﬂict

of

interest

Theauthorshavenoconﬂictofinteresttodeclare.

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