Hyperammonemia.Hyperammonemia.

NaeemNaeem AslamAslam.. FellowFellow--20102010 Univ.Univ. ofof Louisville.Louisville. KYKY ContentsContents ofof discussion.discussion.

„ InterestingInteresting Case.Case.

„ CausesCauses ofof highhigh ammoniaammonia (cirrhosis(cirrhosis isis notnot onlyonly cause)cause)

„ MetabolismMetabolism ofof ammonia.ammonia.

„ DiscussionDiscussion aboutabout thethe case.case. CaseCase

„ 3939 yrsyrs oldold AAFAAF withwith h/oh/o GastricGastric bypassbypass (type(type 1)1) surgerysurgery inin 20082008 admittedadmitted forfor reversalreversal ofof bypassbypass surgery.surgery.

„ MultipleMultiple admissionsadmissions inin thethe pastpast forfor excessiveexcessive weightweight loss,loss, weaknessweakness andand peripheralperipheral neuropathiesneuropathies secondarysecondary toto weightweight loss.loss. „ WeighedWeighed aroundaround >> 400400 poundspounds inin 03/0803/08

„ WeighedWeighed 225225 poundspounds inin 04/0904/09

„ PatientPatient waswas diagnoseddiagnosed withwith multiplemultiple vitaminvitamin deficienciesdeficiencies includingincluding B12,B12, copper,copper, ironiron andand thiaminethiamine andand beingbeing supplemented.supplemented. „ OtherOther issuesissues Anasarca.Anasarca. AnemiaAnemia ofof chronicchronic disease.disease. WeaknessWeakness-- usesuses canecane toto walk.walk.

PMHPMH ObesityObesity s/ps/p gastricgastric bypassbypass „ PreviousPrevious admission.admission. HadHad elevatedelevated LFtsLFts andand foundfound toto havehave elevatedelevated ammoniaammonia level.level. StartedStarted onon LactuloseLactulose andand carnitorcarnitor.. S/pS/p LiverLiver biopsybiopsy „ LiverLiver biopsybiopsy 04/0904/09 AcuteAcute andand chronicchronic cholestasischolestasis andand panlobularpanlobular macrovesicularmacrovesicular steatosis.steatosis. Mod.Mod. PortalPortal inflammationinflammation withwith lymphocyteslymphocytes andand histiocytes.histiocytes. „ PSHPSH GastricGastric bypassbypass surgery.surgery. CC--sections.sections.

SocialSocial historyhistory-- NoNo smoking,smoking, nono alcoholalcohol andand nono drugs.drugs. „ Medications.Medications.

Vitamin B1 250 mg once a day. Vitamin B12 Calcium citrate plus D Iron MVI ASA Copper 2 mg PO once a day. Carnitor 330 mg PO BID Prilosec. Lortabl Exam.Exam.

„ P.P. 100100 BPBP 131/87131/87 RRRR 2020 satssats 98%98% WastingWasting--temporal.temporal. ProminentProminent bonesbones aroundaround clavicularclavicular andand spinespine area.area. AlertAlert orientedXorientedX 33 CVSCVS s1s1 s2s2 ChestChest clearclear Abdomen,Abdomen, distended,distended, fluidfluid thrillthrill ++ EdemaEdema 2+2+ b/lb/l CNS.CNS. AlertAlert orientedoriented X3X3 4/54/5 allall limbs.limbs. „ WBC 11.75 „ HB 11.5 MCV 86 „ Plt 346 „ N 75% „ Total Bili 3.6 Direct 1.4 „ AST/ALT 62/62 Albumin 1.9 „ Alk. Phosph. „ PT 17.9 „ INR. 1.9 „ PTT 32.7 HospitalHospital coursecourse

„ AdmittedAdmitted toto getget reversalreversal ofof gastricgastric bypass.bypass.

„ StartedStarted onon TPNTPN toto buildbuild up.up. TPNTPN -- 12251225 CalCal 6060 GMGM AAAA Dextrose.Dextrose. 635635 KcalKcal LipidLipid 350350 KcalKcal 80%80% patientpatient estimatedestimated Kcal.Kcal. EnsureEnsure supplementssupplements BID.BID. th „ OnOn 44 dayday ofof hospitalizationhospitalization patientpatient gotgot confusedconfused andand GIGI consultedconsulted forfor highhigh AmmoniaAmmonia level.level.

„ PatientPatient gotgot moremore worseworse andand unresponsiveunresponsive withwith AmmoniaAmmonia ofof 300300 andand transferredtransferred toto ICU.ICU. LabsLabs atat thatthat time.time.

„ Na 138 ABG 7.5/44/64/34/94%

„ K 4.4 PT/INR 16.5/1.7

„ CO2 31

„ BUN/CRT 12/0.6

„ Glucose 89

„ Total Bil. 3.8

„ AST/ALT 34/30

„ Alk Phosp 155

„ Ammonia 300

„ WBC 10.92

„ HB 10.6

„ PLT 210

„ N 79 MRIMRI Head.Head.

„ NoNo evidenceevidence ofof acuteacute infarct.infarct.

„ NoNo abnormalabnormal intensityintensity oror enhancementenhancement presentpresent withinwithin thethe brainbrain parenchyma.parenchyma.

„ NoNo significantsignificant abnormalabnormal T1T1 signalsignal seenseen withinwithin basalbasal ganglia.ganglia.

„ EEG.EEG. MetabolicMetabolic encephalopathy.encephalopathy. „ Folate.Folate. 8.08.0 (3(3--16)16)

„ B12B12 >> 21002100

„ CeruloplasminCeruloplasmin 1414 (17(17--54)54)

„ CopperCopper 7878 (80(80--155)155)

„ SeleniumSelenium 3030 (23(23--190)190)

„ ZincZinc 3131 5252 (60(60--120)120)

„ ThiamineThiamine

„ CarnitineCarnitine ??

„ History.History. ReviewReview ofof history.history. AdmittedAdmitted beforebefore-- GotGot TPNTPN andand ammoniaammonia wentwent up.up.

„ Biopsy.Biopsy. AbnormalAbnormal butbut notnot cirrhotic.cirrhotic.

„ ?? „ UREAUREA CYCLECYCLE DEFECTDEFECT ??

„ SerumSerum AminoacidAminoacid panelpanel andand urineurine aminoacidsaminoacids sent.sent.

„ TPNTPN stopped.stopped.

„ StartedStarted onon buphenylbuphenyl.. AmmoniaAmmonia startedstarted comingcoming down.down. PatientPatient gotgot moremore responsiveresponsive onon secondsecond day.day.

„ GeneticGenetic counselercounseler consulted.consulted. ÆÆ TubeTube FeedFeed dietdiet ofof 6060 gmsgms ofof proteinprotein perper day.day. 50%50% ofof protein.protein. NaturalNatural proteinprotein (ensure/boost)(ensure/boost) 50%50% providedprovided throughthrough specializedspecialized formulaformula CyclinexCyclinex--22 (essential(essential aminoamino acids)acids) ÆÆ BuphenylBuphenyl ÆÆ Citrulline.Citrulline. Protein (L-amino acids), carbohydrates (corn syrup solids), fat (high oleic safflower, coconut, soy oils), L-carnitine, taurine, iron (ferrous sulfate), vitamins, minerals; contains phenylalanine; nonessential amino-acid free. „ Corn Syrup Solids, High Oleic Safflower Oil, Coconut Oil, Sodium Citrate, Soy Oil, L- „ EssentialEssential AAAA Leuccine,ine, L-Lysine Acetate, L-Valine, Calcium Phosphate, L-Isoleucine, Magnesium Phosphate, phenylalaninephenylalanine,, valinevaline,, Potassium Chloride, L-Tyrosine, L-Threonine, L-Phenylalanine, Silicon Dioxide, DATEM*, threoninethreonine,, tryptophantryptophan,, Potassium Citrate, Potassium Phosphate, L- Cystine Dihydrochloride, L-Histidine, L- isoleucineisoleucine,, methioninemethionine,, Methionine, L-Tryptophan, L-Carnitine, Calcium Carbonate, Ascorbic Acid, Taurine, leucineleucine,, andand lysinelysine Choline Chloride, m-Inositol, Ferrous Sulfate, Zinc Sulfate, Niacinamide, dl-Alpha-Tocopheryl Acetate, Calcium Pantothenate, Ascorbyl Palmitate, Mixed Tocopherols, Cupric Sulfate, Manganese Sulfate, Thiamine Chloride Hydrochloride, Vitamin A Palmitate, Riboflavin, Pyridoxine Hydrochloride, Folic Acid, Potassium Iodide, Chromium Chloride, Beta- Carotene, Biotin, Sodium Selenate, Phylloquinone, Sodium Molybdate, Vitamin D3, and Cyanocobalamin. SERUMSERUM AMINOACID.AMINOACID.

„ ALANINE. ISOLEUCINE. „ ARGININE. LEUCINE. „ ASPARTIC ACID. LYSINE. „ CITRULLINE. METHIONINE. „ CYSTINE. ORNITHINE. „ GLUTAMIC ACID PROLINE. „ GLUTAMINE SERINE. „ GLYCINE. TAURINE. „ HISTIDINE „ HOMOCYSTINE. „ HYDROXYPROLINE. 2424 URINEURINE

„ OROTIC ACID SUBERIC ACID „ LACTIC SEBACIC ACID. „ PYRUVIC PHENYLACETIC ACID „ SUCCINIC SUCCINLYACETONE „ FUMARIC „ KETOGLUTARIC „ METHYLMALONIC „ HYDROXYBUTYRIC „ ACETOACETIC „ KETOACIDS. „ ADIPIC ACID „ GLYCINEGLYCINE ÆÆ 724724 (140(140--490)490)

„ GLUTAMINEGLUTAMINE ÆÆ 32103210 (410(410--700)700)

„ CITRULLINECITRULLINE ÆÆ 15,15, 11(1011(10--60)60)

„ ARGININEARGININE ÆÆ 5959 (40(40--160)160)

„ ORNITHINEORNITHINE ÆÆ 4848 (20(20--135)135) „ ISOLEUCINEISOLEUCINE -- LOWLOW

„ LEUCINELEUCINE -- LOWLOW

„ LYSINELYSINE -- HIGHHIGH

„ SERINESERINE -- HIGH.HIGH. „ GLYCINE Æ 724 (140-490)

„ GLUTAMINE Æ 3210 (410-700)

„ CITRULLINE Æ 15, 11(10-60)

„ ARGININE Æ 59 (40-160)

„ ORNITHINE Æ 48 (20-135) URINE.URINE.

„ OROTICOROTIC ACID.ACID. 8.08.0 (.8(.8--2.7)2.7) GeneticGenetic testing.testing.

„ BloodBlood sample.sample.

„ OTCOTC deficiencydeficiency--GeneGene deletion/duplication.deletion/duplication. SequenceSequence analysisanalysis diddid notnot identifyidentify mutation.mutation.

OTCOTC FullFull GeneGene squencingsquencing.. OneOne homozygoushomozygous (2(2 copies)copies) variantvariant cc 137137 AA--GG inin thethe OTCOTC genegene .. RepeatRepeat AAAA panelpanel inin 66 weeksweeks

„ Citrulline.Citrulline. 107107 HH (10(10--60)60)

„ ArginineArginine 105105 (40(40--105)105)

„ OrnithineOrnithine 105105 (20(20--135)135)

„ GlutamineGlutamine 368368 LL (410(410--700)700)

„ GlycineGlycine 332332 (140(140--490)490) „ LiverLiver biopsy.biopsy. 09/200909/2009 MacrovesicularMacrovesicular steatosissteatosis portalportal andand pericellularpericellular fibrosisfibrosis andand progressiveprogressive cholestasis.cholestasis.

CommentComment byby pathologist.pathologist. FattyFatty changechange andand pericellularpericellular fibrosisfibrosis hashas beenbeen reportedreported asas possiblepossible featurefeature ofof OTCOTC deficiency.deficiency. AscitesAscites fluidfluid

„ FluidFluid protein.protein. 647647 mg/dlmg/dl

„ FluidFluid AlbuminAlbumin <1.5<1.5

„ WBCWBC 66 USGUSG

„ EchogenicEchogenic liverliver withwith slightslight nodularnodular contours.contours. ThisThis maymay representrepresent fattyfatty infilterationinfilteration butbut cirrhosiscirrhosis cannotcannot bebe ruledruled out.out.

„ LargeLarge volumevolume ascites.ascites.

„ GallGall bladderbladder withwith sludge.sludge. DopplerDoppler USG.USG.

„ NonNon occlusiveocclusive thrombusthrombus--portalportal vein.vein.

„ Ascites.Ascites. AmmoniaAmmonia Metabolism.Metabolism. ElevatedElevated Ammonia.Ammonia.

„ Production.Production.

„ Metabolism.Metabolism.

„ ExcretionExcretion .. WhichWhich organorgan isis involvedinvolved inin ammoniaammonia metabolism.?metabolism.? T/FT/F

„ GutGut

„ Kidney.Kidney.

„ Muscle.Muscle.

„ Liver.Liver.

„ Brain.Brain.

„ NoneNone ofof thethe above.above.

„ AllAll ofof thethe above.above. WhichWhich organorgan isis involvedinvolved inin ammoniaammonia metabolism.?metabolism.? T/FT/F

„ GutGut

„ Kidney.Kidney.

„ Muscle.Muscle.

„ Liver.Liver.

„ Brain.Brain.

„ NoneNone ofof thethe above.above.

„ AllAll ofof thethe above.above. True.True. ►► Gut.Gut. ByproductByproduct ofof proteinprotein digestiondigestion andand bacterialbacterial metabolism.metabolism.

►► Kidneys.Kidneys. EssentialEssential forfor renalrenal handlinghandling ofof acid.acid. AmmoniumAmmonium isis synthesizedsynthesized fromfrom glutamineglutamine (proximal(proximal tubule)tubule) eithereither releasedreleased intointo systemicsystemic circulationcirculation oror excreted.excreted.

(Hyperammonemia in the ICU. Chest. 2007:132:1368-1378) ►►SkeletalSkeletal muscle.muscle. SeizuresSeizures oror intenseintense exerciseexercise increasedincreased ammoniaammonia production.production.

AmmoniaAmmonia degradation.degradation.

„ LiverLiver isis primarilyprimarily responsibleresponsible forfor ammoniaammonia degradation.degradation.

„ AmmoniaAmmonia isis metabolizedmetabolized byby ureaurea cycle.cycle.

„ InIn casecase liverliver doesdoes notnot metabolizemetabolize oror moremore ammoniaammonia whichwhich liverliver cancan handlehandle eliminationelimination isis dependentdependent onon thethe kidneys,kidneys, musclemuscle andand brain.brain. „ Kidneys.Kidneys. IncreaseIncrease urinaryurinary excretionexcretion ofof ammonia.ammonia.

„ MuscleMuscle andand brain.brain. MetabolizeMetabolize ammoniaammonia toto glutamine.glutamine. BrainBrain andand glutamine.glutamine.

„ AcuteAcute riserise inin ammoniaammonia.. AstrocytesAstrocytes rapidlyrapidly metabolizemetabolize ammoniaammonia toto glutamineglutamineÆÆ increasedincreased intracellularintracellular osmolarityosmolarityÆÆ cerebralcerebral edemaedema ++ inflammatoryinflammatory cytokinecytokine releasereleaseÆÆ ApoptosisApoptosis ExcessiveExcessive activationactivation ofof NMDANMDA (glutamate)(glutamate) receptorsreceptorsÆÆ neuronalneuronal degenerationdegeneration andand death.death. MechanizmMechanizm ofof CNSCNS injury.injury.

„ IntracerebralIntracerebral accumulationaccumulation ofof glutamineglutamine isis thethe majormajor causecause ofof encephalopathy.encephalopathy.

„ HighHigh levellevel ofof ammoniaammonia resultresult inin conversionconversion ofof glutamateglutamate toto glutamineglutamine byby glutamineglutamine synthetasesynthetase whichwhich occursoccurs inin astrocytes.astrocytes.

„ IncreasedIncreased intracellularintracellular osmolalityosmolality resultsresults inin astrocyticastrocytic swelling,swelling, brainbrain edemaedema andand cerebralcerebral hypoperfusion.hypoperfusion. RoleRole ofof MRIMRI inin AcuteAcute HyperammonemicHyperammonemic Encephalopathy.Encephalopathy.

„ FourFour groups.groups. a. Diffuse cerebral Edema followed by diffuse cerebral atrophy. b. Extensive infarct like abnormality presenting as acute hemiplegia. c. Ischemic lesions in cerebral vascular territory. d. Reversible symmetric cortical involvement of cingulate gyri, temporal lobes and insular cortex.

(Takanashi J. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorder. Am J Neuroradiology) . A, Image done on admission to the community hospital. B, Image done 24 hours later demonstrates bilateral hemispheric edema with effacement of cerebrospinal fluid spaces Hyperammonemia in OTC deficient patient. VenousVenous oror ArterialArterial Ammonia.?Ammonia.?

WhichWhich isis betterbetter toto checkcheck ?? VenousVenous oror ArterialArterial Ammonia.?Ammonia.?

►► LiverLiver isis working.working. VenousVenous andand arterialarterial ammoniaammonia dodo notnot correlate.correlate. AsAs liverliver metabolizemetabolize venousvenous ammonia.ammonia.

►► FulminantFulminant hepatichepatic failurefailure.. VenousVenous ammoniaammonia correlatecorrelate withwith ArterialArterial ammonia.ammonia. ArterialArterial ammoniaammonia correlatecorrelate withwith brainbrain glutamineglutamine levellevel whichwhich correlatecorrelate withwith developmentdevelopment ofof ICHICH (intracranial(intracranial Hypertension).Hypertension). ConsultConsult ofof increasedincreased ammonia.ammonia.

„ IncreasedIncreased ammoniaammonia production.production.

„ DecreaseDecrease AmmoniaAmmonia elimination.elimination. IncreasedIncreased ammoniaammonia production.production.

„ High protein load and increased catabolism. „ Seizures. „ Trauma or burns. „ Steroid administration. „ Starvation. „ GI hemorrhage. „ TPN „ Urease producing bacteria (proteus, klebsiella) infection. „ Severe exercise. „ Chemotherapy. „ Cancers. (multiple Myeloma) DecreasedDecreased AmmoniaAmmonia Elimination.Elimination.

„ LiverLiver Failure.Failure.

„ TIPS.TIPS.

„ Drugs.Drugs.

„ InbornInborn errorserrors ofof metabolism.metabolism. UreaUrea cyclecycle disorders.disorders. OrganicOrganic acidurias.acidurias. DrugsDrugs associatedassociated withwith HyperammonemiaHyperammonemia

A. DrugsDrugs causingcausing liverliver failure.failure.

B. DrugsDrugs associatedassociated withwith UCDsUCDs.. Glycine. Salicylates. Valproate. Carbamezipine. Sulfadiazine. Pyrimethamine. WorkWork upup forfor highhigh AmmoniaAmmonia

„ HistoryHistory isis veryvery important.important.

„ RuleRule outout liverliver disease.disease. Blood/ImagingBlood/Imaging

„ TwoTwo conditionsconditions cancan coco--exist.exist.

„ Medications.Medications.

„ ConsiderConsider inborninborn errorserrors ofof metabolism.metabolism. UREAUREA CYCLE.CYCLE.

UREAUREA cyclecycle disorders.disorders.

„ CarbamylCarbamyl phosphatephosphate synthetasesynthetase deficiency.deficiency.

„ OrnithineOrnithine transcarbamylasetranscarbamylase deficiency.deficiency.

„ ArginosuccinateArginosuccinate synthetasesynthetase deficiency.deficiency.

„ ArginosuccinateArginosuccinate lyaselyase deficiency.deficiency.

„ NN--acetylacetyl glutamateglutamate synthetasesynthetase deficiency.deficiency.

„ ArginaseArginase deficiency.deficiency. „ Epidemiology.Epidemiology. 11 inin 82008200 livelive birthsbirths

Pathophysiology.Pathophysiology. UreaUrea cyclecycle convertsconverts nitrogennitrogen fromfrom peripheralperipheral (muscle)(muscle) andand enteralenteral sourcesource (protein(protein ingestion)ingestion) intointo ureaurea thatthat isis waterwater solublesoluble andand excreted.excreted. „ TwoTwo molesmoles ofof nitrogennitrogen oneone fromfrom ammoniaammonia andand oneone fromfrom aspartateaspartate areare convertedconverted toto ureaurea inin eacheach cycle.cycle.

„ AmmoniaAmmonia nitrogennitrogen derivesderives fromfrom circulatingcirculating aminoacidsaminoacids,, mostlymostly glutamineglutamine andand alanine.alanine.

„ AspartateAspartate isis aa substratesubstrate forfor arginosuccinicarginosuccinic acidacid synthesis.synthesis. „ NAGsNAGs,, OTC,OTC, CPSCPS areare locatedlocated inin mitochondria,mitochondria, primaryprimary mitochondrialmitochondrial diseasedisease maymay affectaffect ureaurea cyclecycle activity.activity. Genetics.Genetics.

„ AllAll UCDsUCDs areare autosomalautosomal recessiverecessive exceptexcept „ OTCOTC deficiencydeficiency-- XX linked.linked.

AllAll femalefemale offspringsoffsprings ofof aa malemale OTCOTC--deficientdeficient parentparent willwill carrycarry anan OTCOTC mutationmutation andand 50%50% ofof allall offspringoffspring fromfrom aa femalefemale OTCOTC deficientdeficient willwill carrycarry thethe mutation.mutation. „ 10%10% ofof femalefemale carrierscarriers ofof OTCOTC becomebecome symptomatic.symptomatic.

„ ClinicalClinical severityseverity inin affectedaffected femalesfemales dependsdepends onon thethe patternpattern ofof XX--inactivationinactivation inin thethe liverliver (lyonization)(lyonization) andand rangesranges fromfrom asymptomaticasymptomatic toto severelyseverely symptomatic.symptomatic.

„ HemizygousHemizygous malesmales usuallyusually areare moremore severelyseverely affectedaffected thanthan areare thethe heterozygousheterozygous females.females. ClinicalClinical presentation.presentation.

„ MostlyMostly seenseen inin newborns.newborns. PartialPartial enzymeenzyme deficiencydeficiency maymay becomebecome symptomaticsymptomatic laterlater inin life.life.

„ TypicalTypical symptoms.symptoms. OnceOnce feedingfeeding isis startedstarted (human(human oror infantinfant formula)formula) SomnolenceSomnolence andand poorpoor feeding.feeding. Vomiting.Vomiting. Lethargy.Lethargy. Coma.Coma. Æ HyperventillationHyperventillation (cerebral(cerebral edema)edema) thenthen hypoventillationhypoventillationÆÆabnormalabnormal posturingposturing andand respresp.. arrest.arrest. ÆÆAtypicalAtypical presentation.presentation. PartialPartial enzymeenzyme deficiencies.deficiencies. ChronicChronic vomiting,vomiting, developmentaldevelopmental delay,delay, seizureseizure disorder,disorder, headache,headache, lethargy.lethargy. ÆÆ ProteinProtein intake/catabolicintake/catabolic statestateÆÆmakemake themthem worse.worse.

ÆÆ PreferPrefer vegetarianvegetarian diet.diet. WhenWhen dodo youyou suspectsuspect ureaurea cyclecycle disorder.disorder.

„ ElevatedElevated ammoniaammonia withwith normalnormal LFTsLFTs.. „ LabsLabs toto bebe ordered.ordered. SerumSerum ammonia.ammonia. ABGsABGs UrineUrine organicorganic acids.acids. NormalNormal SerumSerum AAAA UrinaryUrinary oroticorotic acid.acid. GeneticGenetic causescauses ofof Hyperammonemia.Hyperammonemia.

„ OrganicOrganic acidemiasacidemias resultresult fromfrom inhibitioninhibition ofof oneone ofof thethe ureaurea cyclecycle enzymesenzymes.. (metabolic(metabolic acidosis/andacidosis/and oror ketoticketotic hypoglycemia)hypoglycemia)

„ FattyFatty oxidationoxidation defectsdefects.. NonNon-- ketoticketotic hypoglycemia.hypoglycemia.

„ DisordersDisorders ofof pyruvatepyruvate metabolism.metabolism. LacticLactic acidemiaacidemia usuallyusually seen.seen. Clinical approach to a newborn infant with symptomatic hyperammonemia. (Kliegman) RareRare causescauses

„ HHHHHH syndrome.syndrome. (Hyperornithinemia,(Hyperornithinemia, hyperammonemia,hyperammonemia, homocitrullinemiahomocitrullinemia.).) ImpairedImpaired transporttransport ofof ornithineornithine acrossacross innerinner mitochondrialmitochondrial membrane.membrane. PresentsPresents withwith Lethargy,Lethargy, hypotoniahypotonia andand seizures.seizures.

„ THANTHAN (transient(transient hyperammonemiahyperammonemia ofof thethe newborn)newborn) –– LowLow birthbirth weightweight ,, respiratoryrespiratory distress.distress. LabLab evaluation.evaluation.

„ ElevatedElevated ammonia.ammonia. (( arterialarterial oror venous.)venous.)

ChilledChilled tubestubes withwith ammoniaammonia--freefree sodiumsodium heparinheparin (green(green top)top) oror EDTAEDTA (purple(purple top),top), placedplaced onon ice.ice. AmmoniaAmmonia Levels.Levels.

AmmoniaAmmonia levellevel higherhigher inin newborns.newborns. HealthyHealthy termterm infantinfant-- 4545 meanmean ((uptoupto 9090 micromol/L)micromol/L) AtAt 3232 weekweek pretermpreterm 7171 micromol/Lmicromol/L ChildrenChildren >1>1 monthmonth LessLess thanthan 5050 micromol/lmicromol/l AdultsAdults lessless thanthan 3030 micromol/lmicromol/l „ QuantitativeQuantitative plasmaplasma aminoacidsaminoacids.. „ CitrullineCitrulline level.level. AbsentAbsent oror lowlow inin CPSI,CPSI, OTCOTC oror NAGS.NAGS. „ ArginineArginine isis lowlow „ GlutamineGlutamine isis increased.increased. „ UrineUrine oroticorotic acidacid increasedincreased inin OTCOTC normalnormal 11--1111 micromol/molmicromol/mol creatinine)creatinine) ,Low,Low inin CPSCPS Increased Glycine and Glutamine.

Low Citrulline Increased Citrulline. Check orotic acid. Check Arginine.

Increased Orotic acid. Normal Orotic acid. Normal Arginine. Increased Arginine. OTC deficiency. CPS deficiency. Urine Arginosucinate Arginine deficiency.

No Arginosuccinate. Citrullinemia

Arginosuccinate in urine Acetylsalicylic acid deficiency

Enzyme Plasma Citrulline Arginosucc Orotic acid Arginine/or deficiency ammonia inate (urine Urine nithine or serum) serum Carbamyl High Low Low Low Low phosphate synthetase OTC High Low Low High Low

Arginosucc High High Low Normal or Low inate high synthetase Arginosucc High High High Normal or Low inase high Arginase High High High Normal or High high EnzymeEnzyme analysisanalysis

„ LiverLiver biopsy:biopsy: CPSiCPSi,, OTCOTC andand NAGsNAGs deficiency.deficiency.

„ FibroblastsFibroblasts fromfrom skinskin biopsy.biopsy. ASSASS andand ASLASL deficiency.deficiency.

„ RedRed bloodblood cells:cells: ArginaseArginase deficiency.deficiency.

(Levels(Levels maymay bebe normal)normal) SpecializedSpecialized testingtesting (research)(research)

AllopurinolAllopurinol test.test. MeasurementMeasurement ofof urinaryurinary oroticorotic acidacid afterafter administrationadministration ofof allopurinol.allopurinol. MildMild casescases maymay havehave minimalminimal elevation.elevation. IncreasedIncreased excretionexcretion maymay occuroccur inin mitochondrialmitochondrial diseasedisease limitinglimiting specificity.specificity. DNADNA mutationmutation analysis.analysis.

MoreMore thanthan 150150 mutationsmutations mostlymostly singlesingle basebase substitutions.substitutions.

„ OTCOTC isis mostmost commoncommon DNADNA testingtesting shouldshould bebe consideredconsidered ifif plasmaplasma AAAA isis notnot diagnostic.diagnostic.

„ FalseFalse negativenegative resultsresults ((microdeletionsmicrodeletions).).

„ FailureFailure toto detectdetect aa pathogenicpathogenic mutationmutation doesdoes notnot excludeexclude thethe diagnosis.diagnosis. PrenatalPrenatal testing.testing.

11.. DNADNA analysisanalysis.. (if(if mutationmutation isis known)known) OTCOTC andand CPSICPSI deficiency.deficiency.

22.. BiochemicalBiochemical testingtesting.. ASSASS andand ASLASL enzymeenzyme activityactivity cancan bebe measuredmeasured inin amniocytesamniocytes andand chorionicchorionic villusvillus cells.cells. ManagementManagement ofof UreaUrea cyclecycle disordersdisorders

► StartStart treatmenttreatment asas soonsoon asas UCDUCD isis suspectedsuspected.. ►► RehydrationRehydration withwith goodgood urineurine output.output. ►► RemoveRemove nitrogennitrogen Medicines and hemodialysis Decrease or stop protein intake. Minimize catabolism. Stimulate anabolism and uptake of nitrogen precursors by muscle. ►► ControlControl infection.infection. ►► Avoid.Avoid. Steroids.Steroids. IncreaseIncrease catabolism.catabolism. ValproicValproic acidacid.. DecreaseDecrease ureaurea cycle,cycle, andand increaseincrease ammoniaammonia level.level. „ Hemodialysis.Hemodialysis. ForFor severesevere hyperammonemia.hyperammonemia. ContinousContinous ArteriovenousArteriovenous oror VenovenousVenovenous hemodialysishemodialysis (CAVHD(CAVHD oror CVVHD)CVVHD) withwith flowflow ratesrates >> 4040--6060 ml/minml/min PharmacologicPharmacologic therapytherapy

„ RemovalRemoval ofof GlutamineGlutamine andand GlycineGlycine toto reducereduce totaltotal nitrogennitrogen pool.pool.

- PhenylacetatePhenylacetate combinecombine withwith glutamineglutamine toto formform PhenylacetylglutaminePhenylacetylglutamine..

- BenzoateBenzoate combinescombines withwith glycineglycine toto formform hippurate.hippurate.

- BothBoth phenylacetylglutaminephenylacetylglutamine andand hippuratehippurate areare waterwater solublesoluble andand excretedexcreted inin urine.urine. AmmonulAmmonul (sodium(sodium phenylacetatephenylacetate--sodiumsodium benzoate)benzoate)

„ ApprovedApproved inin 20052005 forfor parenteralparenteral delivery.delivery.

<20<20 KgKg loadingloading dosedose ofof 500500 mg/kgmg/kg inin aa volumevolume ofof 2525--3535 ml/kgml/kg ofof 10%10% dextrosedextrose infusedinfused overover 9090 minutes.minutes.

>20>20 Kg,Kg, dosingdosing isis basedbased onon surfacesurface area.area. LoadingLoading dosedose isis 1111 g/m2g/m2 „ MaintenanceMaintenance infusioninfusion isis continuedcontinued untiluntil oraloral medicationsmedications cancan bebe tolerated.tolerated. (500(500 mg/kgmg/kg perper 2424 hrshrs << 2020 Kg.Kg. 1111 g/m2g/m2 perper 2424 hrshrs forfor >> 2020 Kg)Kg) „ AdverseAdverse EffectsEffects ofof AmmonulAmmonul.. Metabolic.Metabolic. Hypokalemia,Hypokalemia, Hyperchloremia,Hyperchloremia, acidosis)acidosis) NeurologicNeurologic (seizures)(seizures) RespResp.. distress/failure.distress/failure. BuphenylBuphenyl ((SodiumSodium phenylbutyratephenylbutyrate)) „ TheThe usualusual dailydaily dosedose ofof BUPHENYLBUPHENYL TabletsTablets andand PowderPowder is:is: 450450 –– 600600 mg/kg/daymg/kg/day forfor patientspatients <20<20 kg,kg, oror >9.9>9.9 –– 13.013.0 g/m2/dayg/m2/day inin largerlarger patients.patients. AdverseAdverse EventsEvents ofof BuphenylBuphenyl

„ Amenorrhea/menstrualAmenorrhea/menstrual dysfunction.dysfunction.

„ DecreasedDecreased appetiteappetite occurredoccurred inin 4%4% ofof allall patients.patients.

„ BodyBody odorodor (probably(probably causedcaused byby thethe metabolitemetabolite phenylacetate)phenylacetate) andand badbad tastetaste oror tastetaste aversionaversion werewere eacheach reportedreported inin 3%3% ofof patients.patients. „ Metabolic: acidosis (14%), alkalosis and hyperchloremia (each 7%), hypophosphatemia (6%), hyperuricemia and hyperphosphatemia (each 2%), and hypernatremia and hypokalemia (each 1%)

„ Nutritional: hypoalbuminemia (11%) and decreased total protein (3%)

„ Hepatic: increased alkaline phosphatase (6%), increased liver transaminases (4%), and hyperbilirubinemia (1%)

„ Hematologic: anemia (9%), leukopenia and leukocytosis (each 4%), thrombocytopenia (3%), and thrombocytosis (1%) ArginineArginine

„ DecreasedDecreased formationformation ofof ArginineArginine makingmaking itit essentialessential aminoacidaminoacid..

„ ArginineArginine deficiencydeficiency leadsleads toto cataboliccatabolic statestate resultingresulting inin moremore proteinprotein breakdownbreakdown andand mobilizationmobilization ofof nitrogen.nitrogen.

„ DecreaseDecrease formationformation ofof ornithine,ornithine, citrullinecitrulline andand ArginosuccinicArginosuccinic aced.aced. ProvidingProviding argininearginine generategenerate thesethese waterwater--solublesoluble compoundscompounds thatthat cancan bebe excretedexcreted andand resultsresults inin removalremoval ofof NH3NH3 „ DoseDose IVIV ArginineArginine hydrochloride.hydrochloride. LoadingLoading dosedose <20<20 KgKg loadingloading dosedose 600600 mg/kgmg/kg dissolveddissolved inin 2525--3535 ml/kgml/kg ofof 10%10% dextrosedextrose infusedinfused overover 9090 minutes.minutes. >20>20 kgkg loadingloading dosedose isis 1212 g/m2g/m2 „ MaintenanceMaintenance dose.dose. 200200 mg/kgmg/kg perper 2424 hrs.hrs. <20<20 kgkg 44 g/m2g/m2 perper 2424 hrshrs >20>20 KgKg

ForFor ASSASS andand ASLASL deficiencydeficiency higherhigher maintenancemaintenance dosedose ofof 600600 mg/kgmg/kg usedused toto increaseincrease generationgeneration ofof citrullinecitrulline andand ArginosuccinicArginosuccinic acid.acid. CitrullineCitrulline

„ OTCOTC andand CPSCPS deficiency.deficiency. OralOral dosedose ofof citrullinecitrulline 150150--250250 mg/kgmg/kg perper 2424 hrshrs <20<20 kgkg 33--44 g/m2g/m2 perper 2424 hrshrs >> 2020 kg.kg. WhatWhat toto monitormonitor duringduring therapytherapy

Æ Electrolytes and routine labs. Potassium and sodium. Æ Ammonia every hour during dialysis and once stable below 200 micrmol/L for 24 hrs measurement can be reduced to every 4 hrs.

Æ Serum Aminoacids are measured (daily) to assess efficacy of glutamine removal and to determine replacement of Arginine or citrulline ProteinProtein Restriction.Restriction.

„ Infants..Infants.. 22--2.52.5 gm/kggm/kg perper dayday

„ Adults.Adults. 0.60.6--0.80.8 gm/kggm/kg ChildrenChildren requirerequire lessless thanthan recommendedrecommended dailydaily intakeintake ofof proteinprotein forfor normalnormal growgrowth.th. PatientPatient withwith partialpartial deficiencydeficiency ofof ureaurea cyclecycle maymay toleratetolerate greatergreater proteinprotein intake.intake. „ InIn acuteacute hyperammonemiahyperammonemia oraloral feedingfeeding isis discontinueddiscontinued „ CaloriesCalories areare providedprovided byby IVIV administrationadministration ofof lipidslipids andand glucoseglucose andand proteinprotein intakeintake isis stopped.stopped. „ ProteinProtein shouldshould notnot bebe stoppedstopped moremore thanthan 2424--4848 hrshrs afterafter treatmenttreatment toto avoidavoid proteinprotein catabolismcatabolism „ EnteralEnteral feedingfeeding isis initiatedinitiated asas soonsoon asas possiblepossible

„ ProteinProtein freefree formulaformula suchsuch asas MeadMead johnsonjohnson oror RossRoss formulaformula ProphreeProphree inin conjunctionconjunction withwith aminoamino acidacid mixturesmixtures andand cowcow milkmilk basedbased formulas.formulas. (less(less NitrogenNitrogen inin aminoacidaminoacid mixtures)mixtures)

Pro-phree (abbott). Protein free, L carnitine, linolenic acid, vitamins „ MeasureMeasure serumserum levelslevels ofof essentialessential aminoacidsaminoacids (branched(branched chainchain AA,AA, phenylalanine,phenylalanine, lysine).lysine). SamplesSamples areare obtainedobtained 33--44 afterafter feedingfeeding andand repeatedrepeated everyevery 22--33 days.days.

ChronicChronic management.management. WeightWeight andand growthgrowth totaltotal protein,protein, albuminalbumin andand prealbumin.prealbumin. NutritionalNutritional deficienciesdeficiencies followingfollowing BariatricBariatric Surgery:Surgery: WhatWhat havehave wewe learned?learned?

„ Protein Deficiency.

„ Iron deficiency.

„ Vitamin B12 and Folate deficiency.

„ Calcium and Vitamin D deficiency.

„ Thiamine (vit. B1) deficiency.

„ Fat soluble Vit. Def. Vit A, E, K

„ Magnesium.

„ Zinc

„ Selenium.

(Obesity Surgery, 15. 2005) RoutineRoutine laboratorylaboratory testingtesting afterafter malabsorptivemalabsorptive bariatricbariatric surgerysurgery

33 monthsmonths postoperativelypostoperatively.. Complete blood count; glucose; glycosylated hemoglobin[a]; lipids; chemistry group

At 6-month intervals during first 3 years & then once yearly Chemistry ; complete blood count; lipids; ferritin; zinc; copper; magnesium; vitamin A; total 25-hydroxy vitamin D; folate; whole blood thiamine; vitamin B12; 24-hour urinary calcium (Postoperative Metabolic and Nutritional Complications of Bariatric Surgery Gastroenterology Clinics - Volume 39, Issue 1 (March 2010) GeneralGeneral supplementationsupplementation recommendations.recommendations. ((RYGB-Roux Y gastric Bypass, VSG vertical sleeve gastroplasty, AGB- Adjustable Band, BPD- biliopancreatic diversion, BPD-DS –biliopancreatic diversion with duodenal switch)

Multivitamin containing AGB/VSG Once daily folic acid RY GB 1-2 daily BPD-DS 2 daily. Calcium citrate with AGB 1200-1500 mg/day Vitamin D3 RYGB and BPD-DS 1800 mg/day Vitamin D3 RYGB 1000 IU/day BPD-DS 2000 IU/day Vitamin B12 RY GB Orally or 1000 ug/month IM BPD-DS Monitor and start if needed Elemental Iron RYGB and BDP-DS 65 mg elemental iron in mensturating females. Vitamin B1 All procedures Once daily in first 6 months Vit A and Vit K BPD-DS 10,000 IU vitamin A and 300 ug vitamin K LaboratoryLaboratory testingtesting forfor nutritionalnutritional disordersdisorders afterafter bariatricbariatric surgerysurgery

„ Anemia Ferritin; vitamin B12; folate & then consider vitamin A; vitamin E; zinc; copper

„ Neurologic disorders. Vitamin B12; whole blood thiamine & then consider vitamin E; copper; plasma niacin

„ Visual disorders. Vitamin A; vitamin E; whole blood thiamine

„ Skin disorders. Vitamin A; zinc; plasma niacin

„ Edema Selenium; whole blood thiamine; plasma niacin

(Postoperative Metabolic and Nutritional Complications of Bariatric Surgery Gastroenterology Clinics - Volume 39, Issue 1 (March 2010) „

„ ThankThank you.you.