Stones,BonesandotherPoten/alHPNComplica/ons

DouglasL.Seidner,MDDirector,CenterforHumanNutri/onVanderbiltUniversityMedicalCenter

Disclosures

•  Excerptsfrom--->

•  “Bacteria,Bones,andStones:Managing

ChallengingComplica/onsofSBS”

•  ASPEN2018

•  EJohnson,LMatarese,DSeidner

•  Norelevantfinancialdisclosures

HPNComplica/onsthatwillnotbecovered*

•  Infec/on:Systemic,tunnel,exit1,2

•  Hyperandhypoglycemia1,2•  Dehydra/on1•  Catheter:Clot,tear,crackedhub1•  Veininflamma/on1•  Airemboli1•  PNALD(usewebpagesearchengine)

*Available at https://Oley.org 1. On HPN complication chart 2. Resources: My HPN- Online Education

Presenta/onOutline

•  Stones=Nephrolithiasis(kidneystones)•  Bones=Osteoporosisandosteomalacia

•  Bacteria=SIBO&D-Lac/cAcidosis

Nephrolithiasis

Nephrolithiasis•  General Population: 8.4%

– Calcium,Oxalate,Urate,Cysteine,Xanthine,Phosphate

•  Prevalence of symptomatic stones 42-50% after GI ops – Colon-in-continuity: calcium

oxalate – End-jejuno- or ileostomy:

calcium oxalate and uric acid Gut 1992;33:1493-97 Urol Dis Am Eur Urol 2012;62:160-5 NEJM 2004;350:684

RiskFactorsforStoneForma/onSurgicalanatomy Stonetype Predisposingfactors

Jejuno-colicanastomosis***Colonincon)nuity***25%incidenceofstones

Calciumoxalate

-Dehydra8on/LowUrineVolume(allstones)-Increasedamountofluminaloxalated/tlowcalciumconcentra8onsd/tsteatorrhea.-Enhancedcolonicabsorp8ond/tunabsorbedbilesalts,especiallyifTIresec8on<100cm.-Decreasedbacterialdegrada/on-Enhancedproduc/onPyridoxinedeficiencyThiaminedeficiencyGutbacteria?

Jejunostomyorileostomy10-15%incidenceofstones

CalciumoxalateUricacid

-Hypocitraturia-Hypomagnesuria(minor)-LowurinepH

Tomson CRV, Nephrocalcinois and nephrolithiasis. IN: Intestinal Failure. Nightingale J Ed. 2001

UrinaryOxalateExcre/onacerIlealResec/on

•  24-hoururinaryoxalateexcre/on

•  12/18(66%)ofresectedpa/entshadhyperoxaluria

•  3pa/entspassedstones•  Pa/entswiththelargest

resec/ons(ormostextensivedisease)hadthegreatestdegreeofhyperoxaluria

NEJM 1973;289(4):172

EffectofOxalateFreeDietonUrinaryOxalateExcre/on

•  4subjectsw/ilealresec/onandhighUoxalate.

•  24hrurineonthreeconsecu/ve5dayperiods

•  Oxalateexcre/onfelltonormalvalueswithin24hoursofstar/nglowoxalatediet(<4gmvs100-200mg)

•  Returnedtohighvaluesonresump/on

NEJM 1973;289(4):172

HighOxalateFoodsFoodType Examples

Fruits Blackberries,blackraspberries,blueberries,redcurrants,dewberries,figs,grapes,gooseberries,kiwi,lemonpeel,orangepeel,redraspberries,rhubarb,strawberries,tangerines,anyjuicemadefromabovefruits

Vegetables Beans(green,wax,dried),beets(tops,roots,greens),celery,chives,collards,dandelion,eggplant,escarole,kale,leeks,mustardgreens,okra,parsley,parsnips,peppers(green),pokeweed,rutabagas,sorrel,summersquash,sweetpotatoes,Swisschard,tomatosoup,vegetablesoup,watercress,yams

Meatsubs/tutes,beans,nuts,seeds

Almonds,bakedbeanscannedintomatosauce,cashews,greenbeans(waxedanddried),peanutbuker,peanuts,pecans,sesameseeds,sunflowerseeds,tofu(soybeancurd),walnuts

Beverages Anyjuicemadefromhighoxalatefruits,dracbeer,chocolate(plain),chocolatemilk,cocoa,coffeepowder(instant),Oval/ne,tea(brewed)

Starches FigNewtons,fruitcake,grahamcrackers,grits,whitecorn,kamut,soybeancrackers,wheatgerm

Condiments Groundcinnamon,rawparsley,pepper(>1tsp/day),ginger,soysauce

AbilityofDifferentProbio/cStrainstoMetabolizeOxalatesInVitro

•  Oxalate-degradingac/vityof13lactobacilliand5bifidobacteriatested

•  Lactobacillusstrainsweremoreefficientthanbifidobacteriaindegradingoxalates.

•  L.paracaseiLPC09(DSM24243)gavethebestresult,with68.5%ofammoniumoxalateconversionfollowedbyL.gasseriandL.acidophilusspecies.

•  Clinicalu8lityunclear

J Clin Gastroenterol 2014;48:591

Symptoms

•  Paininthelowerback,flank,groin•  Nausea/vomi/ng•  Bloodintheurine•  Painwhenurina/ng•  Unabletourinate,urinaryfrequency•  Fever/chills.•  Foulsmellingorcloudyurine

OtherRiskFactors

•  Medicalcondi/ons– HBP,DM,Gout,Obesity,Malabsorp/on,Parathyroiddisease,Hypercalciuria

•  Medica/ons– Diure/cs,Caantacids,Dilan/n,Cipro,Cecriaxoneandothers

•  Familyhistoryofkidneystones•  Blockageorrepeatinfec/onsoftheUT

Evalua/onandManagement

•  Bloodtests•  Urinesampletest•  Stoneanalysis•  Imagingstudy

–  CT–  US–  IVP–  Plainfilm

•  IVF•  Painmedica/on•  Medica/ontorelaxtheureter

•  Minimally-invasiveprocedures

•  Surgery

MinimizeStoneForma/oninSBSMethods Ra8onale

Adequatefluidandsaltintake(considerNaClsuppl)

InSBSurinevolumeandurinesodiumarereducedduetomalabsorp/on.Increasefluidandsaltintaketoincreaseurineoutputtopreventstoneforma/on.

Lowfatdiet Reducefakyacidsthatbindsintraluminalcalcium!leadstothatleadstoanincreaseinfreeoxalate,(unbound)!increasedabsorp/onofdietaryoxalate.

Calciumsupplementa/on Bindoxalateinthegut.

Cholestyramine Bindsbilesaltsandoxalate,reducingoxalateabsorp/oninthecolon.

Lowoxalatediet Reduceoxalateintaketoreduceoxalateexcre/on.

Lowsodiumandanimalproteinintake

Reduceurinarycalciumexcre/on.(mosthelpfulwithintactGItract)

Potassiumcitratesupplements

Alkalinizeurineandcanpreventsurinarycalciumoxalate,urateandphosphatecrystalforma/on.

Avoidsystema/cacidosis(considerNaHCO3suppl)

Acidosisreducescitrateexcre/onandurinepHwhichcancausecalciumoxalatecrystalforma/onintheurine.

Magnesiumsupplements Hypomagnesemialeadstoreducedcitrateexcre/on(minoreffect,difficultinSBS)

Probio/cs??? Oxalatedegrading.

MetabolicBoneDisease

Osteoporosisvs.Osteomalacia2001 NIH definition OP: A skeletal disorder characterized by compromised bone strength (integration of bone density and bone quality) predisposing of present increased risk of fracture. [fragility fracture] OM: Defective bone mineralization at the bone-osteoid interface with Increased bone volume but increased fracture risk

- Altered vitamin D nutrition or metabolism - Phosphate wasting disorders - Metabolic acidosis - Defective bone mineralization - Inhibitors of bone mineralization

PrevalenceofOsteoporosisinIntes/nalFailureandInsufficiency

Nygaard L, et al. Clin Nutr 2017

P<0.001 comparing Controls to IF and II for O‘osis and O‘penia

RiskFactorsforIF-MBDDiseaseAssociatedFactors

•  Malignancy-cont’d•  Hypogonadism•  Paraneoplas/c

•  IBD–  VitaminDdeficiency

•  Avoidanceofdairy•  Malabsorp/on

–  Cor/costeroids–  Hypogonadism–  Inflammatorycytokines

•  Shortbowelsyndrome–  Malabsorp/on–  Renalcalciumwas/ng–  Metabolicacidosis

•  Diarrhea(non-aniongap)•  D-lac/cacidosis(aniongap)

•  Malignancy–  DiseaseandRxassociated

•  Anorexia•  Malabsorp/on

Seidner DL JPEN 2002

RiskFactorsforIF-MBD

•  Documenteddeficiency– Protein,vitaminD,calcium,magnesium

•  Theore/cdeficiency– VitaminK,vitaminC,copper,fluoride,boron

•  Poten/alPNtoxicity– VitaminA,vitaminE,cadmium,stron/um,vanadium,fluoride(mineralwater)

Ferrone M, Geraci M. NCP 2007

VitaminDStatusinIF/II

•  VitaminDdeficiencyinintes/nalfailure– 96pts:28%mild25-50nmol/l,14%mod<25nmol/l,Nygaard‘17– 186pt:50%mod,26%severe,Napar/vaumnuayN.Nutrients‘17

•  VitaminDdeficiencyinintes/nalinsufficiency– 71pts:31%mild25-50nmol/l,17%mod<25nmol/l,Nygaard‘17– 77pts:44%mod,25%severe,EllegardL.ClinNutr’13– 60pts:65%mod10-20ng/ml,30%sevr<10ng/ml,FanS.NCP’17

PNFactorsthatAffectBoneMineralDensity

•  Increasecalciumexcre8on–  Aminoacid(/tratableacid)

–  Sodium(increaseGFR)–  Calcium–  Dextrose(insulin)–  Cycledinfusion

•  Decreasecalciumexcre8on–  Phosphorus

Seidner DL JPEN 2002 Ferrone M, Geraci M. NCP 2007

PNFactorsthatAffectBoneMineralDensity

•  Adverselyaltersbonemetabolism– Magnesium(low)

•  PTHsecre/onandrenalac/vity•  AbnormalvitaminDmetabolism

– Metabolicacidosis•  Aminoacidsproduceweakorganicacids•  Chronicdiarrhea,d-lac/cacidosis

–  Heparin(modestdoses)–  VitaminD(low,inac/ve)–  Aluminum(any) Seidner DL JPEN 2002

Ferrone M, Geraci M. NCP 2007

Clin Nutr 35 (2016) 247-307

•  Preven/on&TreatmentofIF-MBD*– DiagnosisandmonitorMBDwithDEXAandbiochemistry.(#109-110.grade:low)

– PromptlyaddressriskfactorsforOPinallpa/entsonLT-HPN.(#111.grade:verylow)

– Theprimarystepistoop/mizePNwithrequiredvitaminD,calcium,andphosphate.MedicaltreatmentmayincreaseBMDandlowerfracturerisk.(#112.grade:low)

*Strength of recommendations are all strong

DXAMeasurement(Dual-energyX-rayAbsorp/ometry)

•  Consideredtheclinicalstandard

“GoldStandard”•  MeasuresBMDatmul/plesites

–  Spine–  Hip–  Forearm–  Totalbody

•  CannotddxOPvsOM

Pa/entEvalua/onSerum BMP, Mg, Phos Initial followed qwk for ~3 months iPTH Malabsorption or hyperpara suspect 25-OH vitamin D (1, 25 OH vitamin D)

Malabsorption suspect

TSH Hyperthyroidism suspect C-telopeptide (CTX) Measures bone resorption, monitor

response to tx. (fragments of type I collagen)

Radiographic DEXA** Baseline, every 1 to 3 years, prnUrine 24-hour Ca, Mg Monitor every 6 to 12 months

Evaluation Comment

**Optimally on the same scanner

ManagementofMBD•  EliminatesecondarycausesofMBD

– Treatunderlyingdisease,infec/ons,chronicinflamma/on

– Diagnoseandtreathyperthyroidism,hypogonadism,hyperparathyroidism

– Discon/nuetobaccouse– Minimizealcoholintake– Taperorstopglucocor/coids– Encourageweightbearingexercise

PNPrepara/on•  Calciumgluconate-15meq(3gmsalt)•  Phosphate-serumconcmid-range

– Ca:PO4ra/oor5meq:10mmol– 10-14mmol/1000kcaldextrose

•  Acetate-serumbicarbmid-range•  Sodium–balanceintakewithoutput•  Aminoacids-1.5g/kg/d,reducewhenvisceralproteinsnormalizeandpa/entiswell

ESPENGuidelineCaveats

•  PNAluminumlessthan25mcg/LKleinGLAJCN’95•  SupplementvitDifelevatedPTHandlow25-hydroxyvitDEllegardL.ClinNutr’13

•  ConsidertemporarywithdrawalofvitDiflowBMD,PTHand1,25-OHDVerhageAHJPEN’95– ProvideVitaminD200IU/d=MVI-13

•  ConsiderIVclodronate,pamidronate,zolindronicacid(bisphosphonates)

Medica/onsFDAApprovedforOP

•  Inhibitsosteoclasts(boneresorp/on)– Conjugatedestrogens– Selec/veestrogenreceptormodulators

– Bisphosphonates– Calcitonin– RANKLinhibitors

•  S/mulatesosteoblasts(boneanabolism)

– Parathyroidhormone

Long-termPNDoesNotExacerbateOP

•  56HPN5.5+1.2y•  67%withOP•  T-scoresimproved,espifSBSonset>21yo

Cohen-SolalM.J.BoneMiner.Res.‘03

Long-termPNDoesNotExacerbateOP

•  75HPN4.1+1.9y,4.4+2.9scans,– BMDlossof1%annual(p<.005)nodifferentthanage-andsex-matchedhealthysubjects.

– Modeles/matesofBMDforCDwassignificantlylowerthannon-CD.HaderslevKV.JPEN2004

•  65HPN18.1+5.5mos–  Increaselumbarspine(P=0.04).– Mul/pleregressionfoundLSZ-scoretocorrelatenega/velywithfemalesexagestar/ngHPN.PironiL.ClinNutr2004

SmallIntes/nalBacterialOvergrowth•  Predisposingfactors

– Blindloop,stricture,internalfistula–  Increasedintes/naltransit– Decreasedgastricacid,pancrea/csecre/ons– Absenceofileocecalvalve

•  Consequences– BacteriametabolizeluminalnutrientsANDcausemucosalinjury!diarrhea,gas,bloat/pain

– D-lac/cacidosis!neurologicsymptoms

•  DiagnosisofSIBO–  Intes/nalaspirate:>105CFU/mLofbacteriagrownfromjejunalfluidorthepresenceofcolonicororopharyngealbacterialspecies

–  HydrogenBreathTest:Undigestedsugarincolonproduceexcesshydrogen(unreliableinSBSd/trapidGItransit)

•  Consequences–  NutrientMalabsorp/on

•  Mucosalinflamma/on,villousatrophy•  Deconjugatebilesalts,producelithocholicacid

–  Toxins:•  Ammonia,D-lactate,alcohol,pep/doglycans

–  Symptoms:Poorappe/te,diarrhea,gas,bloa/ng

SymptomswithD-lac/cacidosisPresenta8on Percentage

Encephalopathy 100

Slurredspeech 52

Ataxia 32

Gaitdisturbance 29

Weakness 16

Tachypnea 13

Aggressivebehavior 10

Diarrhea 6

AcuteCHF 3

Headache 3

Nystagmus 3

Blurryvision 3

Explosivespeech 3

Echolalia 3

“Feelingdrunk” 3

Depression 3

•  Postulatedmechanismsforneurologicsymptoms–  Directeffectonbrain–  Otherorganiccompounds

Kowigi. Gastro Res Pract 2015;20:634 Oh. NEJM 1979;301249 Bongaerts Clin Chem 1995;41:107 Godey. AJG 2000;95:3675

ClinicalD-Lac/cAcidosis•  Metabolicacidosiswith>1thefollowing:

– Typicalneurologicsymptoms– SerumD-lac/cacid>3mmol/L,normalL-lactate– Acidosisinducedbyfoodintakethatimproveswithrestric/on

– Recentcomple/onofan/bio/csorini/a/onofprobio/cs

– Nega/veurineAcetest/ketonebodies– CulturebacteriacapableofproducingD-lactate

Uribarri. Medicine 1998;77(2):73

AcuteTreatmentofD-Lac/cAcidosis

•  IVhydra/onwithsodiumbicarbonate•  AvoidRinger’slactatesolu/on•  RestrictenteralCHO,PNasneeded•  Thiamine(B1)supplementa/onforincreasedpyruvatedehydrogenaseac/vity

•  An/bio/csandProbio/csunpredictable•  Inrarecaseshemodialysis

SIBOManagement

•  Surgicalinterven/onifpar/alSBOorboweltapering/lengtheningifdilated

•  Dietmodifica/on– Highcomplexcarbohydrates(CHO),lowsimplesugar,lowfatasneeded(SBSdiet)

– Lowlactose,asneeded– Treatvitaminandmineraldeficiencies(B12,etc.)–  InD-lac/cacidosis,cau/ouslyreintroduceCHO

Quigley, E. Infect Dis Clin N Am 2010;24:943

SIBOManagement

•  An/bio/cs(offlabel)–7daycourse– Amox/Clavulanate500/125mgpo/d,#21,$63– Metronidazole250mgpo/d,#21,$24– Rifaximin550mgpobid,#14,$$$$$

•  Probio/cs(overthecounter)•  Limitan/-secretoryandan/-diarrhealmeds

Quigley, E. Infect Dis Clin N Am 2010;24:943

Conclusion

•  Dietmodifica/on,oralsupplements,andmedica/onsmaybehelpfulinnephrolithiasis,PNassociated-MBD,andSIBO

•  Onlymedica/onsforMBDareFDAapproved

•  ModifyPNtoop/mizebonemetabolism

•  Treatallunderlyingassociateddiseases