Jaundice. In Tens of Minutes 1.0= Normal Vigilance Medical Audience Attention Span.
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Transcript of Jaundice. In Tens of Minutes 1.0= Normal Vigilance Medical Audience Attention Span.
JaundiceJaundice
In Tens of Minutes
1.0
= N
orm
al
Vig
ilan
ce
Medical Audience Attention Span
OverviewOverview
What is “jaundice”?What is “jaundice”? TypesTypes EtiologiesEtiologies DiagnosisDiagnosis
What is jaundice?What is jaundice?
The french word The french word jaune -jaune - yellow. yellow. Icterus - yellowish discolorationIcterus - yellowish discoloration Skin, conjunctiva, sclera, mucous Skin, conjunctiva, sclera, mucous
membranesmembranes Appears 'top to bottom' (face to feet)Appears 'top to bottom' (face to feet) Resolves 'bottom to top'. Resolves 'bottom to top'.
Technical definitionTechnical definition
HyperbilirubinemiaHyperbilirubinemia Normal less than 1.2 mg/mlNormal less than 1.2 mg/ml Less than 5 percent conjugatedLess than 5 percent conjugated Not visual until greater than 2.5 Not visual until greater than 2.5
mg/mlmg/ml Best seen in sclera and oral mucous Best seen in sclera and oral mucous
membranes (look at soft palate)membranes (look at soft palate)
BilirubinBilirubin RBC destructionRBC destruction Hemoglobin degraded to Hemoglobin degraded to
hemeheme Spleen turns into Spleen turns into
unconjugated bilirubinunconjugated bilirubin Transported to liverTransported to liver Conjugated with Conjugated with
glucuronic acidglucuronic acid Passed into bilePassed into bile Small bowel bacteria Small bowel bacteria
convert to stercobilinogenconvert to stercobilinogen Oxidised to stercobilin.Oxidised to stercobilin. Some reabsorbed, Some reabsorbed,
excreted renally as excreted renally as urobilinogenurobilinogen
Oxidised into urobilinOxidised into urobilin
A Tale of Two A Tale of Two HyperbilirubinemiasHyperbilirubinemias
UnconjugatedUnconjugated OverproductionOverproduction Impaired uptakeImpaired uptake Conjugation abnormalitiesConjugation abnormalities
MixedMixed Hepatocellular diseaseHepatocellular disease Impaired canalicular excretionImpaired canalicular excretion ObstructionObstruction
Or…Or…
Pre-hepaticPre-hepatic or or hemolytichemolytic causes causes HemolysisHemolysis
HHepaticepatic causes causes Conjugation problemsConjugation problems
PPost-hepaticost-hepatic or or extrahepaticextrahepatic Excretion of bile disruptedExcretion of bile disrupted
Unconjugated Unconjugated HyperbilirubinemiaHyperbilirubinemia
OverproductionOverproduction HemolysisHemolysis
Extravascular vs intravascularExtravascular vs intravascular ExtravasationExtravasation DyserythropoiesisDyserythropoiesis
Reduced hepatic uptakeReduced hepatic uptake Impaired conjugationImpaired conjugation Physiologic jaundice of newborn Physiologic jaundice of newborn
Consists of all threeConsists of all three
OverproductionOverproduction
Normal liver can keep upNormal liver can keep up Bilirubin < 4-5 mg/dlBilirubin < 4-5 mg/dl Conjugated bilirubin remains 3-5 Conjugated bilirubin remains 3-5
percentpercent Hepatic disease affects canilicular Hepatic disease affects canilicular
excretionexcretion Bilirubin diffuses back into plasmaBilirubin diffuses back into plasma
Conjugation FunctionConjugation Function
Gilbert’sGilbert’s Crigler-NajjarCrigler-Najjar
What about Gilbert?What about Gilbert?
Reduced levels of Reduced levels of Uridinediphosphoglucuronate Uridinediphosphoglucuronate glucuronosyltransferases (UGTs) glucuronosyltransferases (UGTs)
Mutation in the promoter regionMutation in the promoter region Deficiency in isoform that conjugates Deficiency in isoform that conjugates
bilirubin to glucuronic acid bilirubin to glucuronic acid Creates a backflow equilibriumCreates a backflow equilibrium
And Crigler-Najjar?And Crigler-Najjar?
Type I - UGT with no activityType I - UGT with no activity KernicterusKernicterus Fatal without liver transplantFatal without liver transplant
Type II – UGT with reduced activityType II – UGT with reduced activity Less severe than type ILess severe than type I
Genetic lesions in bilirubin-UGT deficiency syndromes
Are you new here?Are you new here?
Conjugating activity low in neonatesConjugating activity low in neonates Turn over of fetohemoglobin to adult Turn over of fetohemoglobin to adult
formsforms May need light therapyMay need light therapy
Other Effects on ActivityOther Effects on Activity Decreased UGT activityDecreased UGT activity
AntibioticsAntibiotics HepatitisHepatitis Chronic hepatitisChronic hepatitis Advanced cirrhosisAdvanced cirrhosis Wilson’s diseaseWilson’s disease HyperthyroidismHyperthyroidism Ethinyl EstradiolEthinyl Estradiol
Increased activityIncreased activity Progestational and estrogenic steroidsProgestational and estrogenic steroids
Conjugated Conjugated HyperbilirubinemiaHyperbilirubinemia
Intrahepatic cholestasisIntrahepatic cholestasis Extrahepatic cholestasis/obstructionExtrahepatic cholestasis/obstruction Hepatocellular injuryHepatocellular injury
Dubin-Johnson Dubin-Johnson Autosomal recessiveAutosomal recessive Human canalicular multispecific organic Human canalicular multispecific organic
anion transporter (cMOAT) mutation anion transporter (cMOAT) mutation (multidrug resistance protein 2 (MRP2))(multidrug resistance protein 2 (MRP2))
Impaired transport Impaired transport Accumulation of hepatocellular pigment. Accumulation of hepatocellular pigment. Rare, Sephardic JewsRare, Sephardic Jews Prevalence 1:1300. Prevalence 1:1300. Life expectancy normalLife expectancy normal Reduced prothrombin and factor VII activityReduced prothrombin and factor VII activity Nonpruritic jaundice in teenage years.Nonpruritic jaundice in teenage years.
Rotor SyndromeRotor Syndrome Rare, Rare, Autosomal RecessiveAutosomal Recessive Mechanism not clearMechanism not clear chronic mixed hyperbilirubinemiachronic mixed hyperbilirubinemia Storage defectStorage defect BenignBenign Labs and histology normalLabs and histology normal Biopsy not requiredBiopsy not required Urinary coproporphyrin 250 to 500% normal, Urinary coproporphyrin 250 to 500% normal,
65% coproporphyrin I 65% coproporphyrin I Dubin-Johnson syndrome - urinary Dubin-Johnson syndrome - urinary
coproporphyrin normal, 80% coproporphyrin I coproporphyrin normal, 80% coproporphyrin I Normal – urinary porphyrins 75% Normal – urinary porphyrins 75%
coproporphyrin IIIcoproporphyrin III
Bilirubin throughput in hepatocytes
ObstructionObstruction
Bilirubin retainedBilirubin retained Glucuronidation reversedGlucuronidation reversed Unconjugated bilirubin diffuses into Unconjugated bilirubin diffuses into
plasmaplasma Mixed bilirubin transported into Mixed bilirubin transported into
plasma by MRP transporters.plasma by MRP transporters.
Primary Sclerosing Cholangitis
Cholangiocarcinoma
Differential DxDifferential Dx
CholelithiasisCholelithiasis Tumors Tumors Primary sclerosing cholangitisPrimary sclerosing cholangitis ParasitesParasites PancreatitisPancreatitis Strictures (benign/malignant)Strictures (benign/malignant) AIDS cholangiopathyAIDS cholangiopathy
AIDS CholangiopathyAIDS Cholangiopathy
CryptosporidiumCryptosporidium CMVCMV HIVHIV Biopsies or bile cultures for dxBiopsies or bile cultures for dx
Other HIV PossibilitiesOther HIV Possibilities Viral HepatitisViral Hepatitis HSVHSV EBVEBV TumorsTumors LymphomaLymphoma Kaposi’sKaposi’s DrugsDrugs
Mycobacterium TBMycobacterium TB Atypical Atypical
mycobacteriummycobacterium FungiFungi CryptococcusCryptococcus HistoplasmaHistoplasma CandidaCandida CoccidioidesCoccidioides Pneumocystis Pneumocystis
cariniicarinii
Intrahepatic CholestasisIntrahepatic Cholestasis
JaundiceJaundice Bile ducts are patentBile ducts are patent
EtiologiesEtiologies Viral HepatitisViral Hepatitis Alcoholic Alcoholic
HepatitisHepatitis Non-Alcoholic Non-Alcoholic
SteatohepatitisSteatohepatitis Primary Biliary Primary Biliary
CirrhosisCirrhosis DrugsDrugs ToxinsToxins End-stage liver End-stage liver
diseasedisease
SepsisSepsis Low perfusion Low perfusion
statesstates MalignancyMalignancy Liver infiltrationLiver infiltration TPNTPN Post-operativePost-operative Post-transplantPost-transplant Sickle Cell diseaseSickle Cell disease PregnancyPregnancy
Alcoholic HepatitisAlcoholic Hepatitis
CholestasisCholestasis FeverFever LeukocytosisLeukocytosis History of EtOHHistory of EtOH AST to ALT exceeds 2.0AST to ALT exceeds 2.0 AST and ALT each less than 500AST and ALT each less than 500
NASHNASH Similar to EtOH Similar to EtOH
but but NO NO EtOHEtOH ObesityObesity DMDM FemaleFemale
AmiodaroneAmiodarone Antiviral drugsAntiviral drugs
((nucleoside analogues) nucleoside analogues) Aspirin / NSAIDS Aspirin / NSAIDS StatinsStatins Corticosteroids Corticosteroids Methotrexate Methotrexate Nifedipine Nifedipine Perhexiline Perhexiline Tamoxifen Tamoxifen Tetracycline Tetracycline Valproic acid Valproic acid
PBCPBC
Cholestatic and hepatocellular injury Cholestatic and hepatocellular injury picturepicture
Antimitochondrial antibodies Antimitochondrial antibodies Present in 95 percentPresent in 95 percent 95 percent sensitive, 98 percent 95 percent sensitive, 98 percent
specificspecific Anti-nuclear antibodies Anti-nuclear antibodies
In 70 percent of patientsIn 70 percent of patients
DrugsDrugs
Dose relatedDose related Allergic reactionsAllergic reactions IdiosyncraticIdiosyncratic Mixed hepatocellular/cholestatic Mixed hepatocellular/cholestatic
picturepicture Thorough drug history Thorough drug history
imperativeimperative
Low Perfusion StatesLow Perfusion States
SepsisSepsis Hyperbilirubinemia can promote sepsisHyperbilirubinemia can promote sepsis
CHFCHF HypotensionHypotension HypoxemiaHypoxemia
Paraneoplastic Paraneoplastic SyndromesSyndromes
Stauffer’s SyndromeStauffer’s Syndrome Uncommon in RCC Uncommon in RCC Absence of metastasesAbsence of metastases Cholestasis, elevated alkaline phosphatase.Cholestasis, elevated alkaline phosphatase. FeverFever Weight lossWeight loss FatigueFatigue Poor prognosisPoor prognosis Related to tumor cytokinesRelated to tumor cytokines Nephrectomy may ameliorate Nephrectomy may ameliorate Recurrence - maybe more cancer or metastasesRecurrence - maybe more cancer or metastases
InfiltrationInfiltration
AmyloidosisAmyloidosis SarcoidosisSarcoidosis LymphomaLymphoma TBTB
TPNTPN
SteatosisSteatosis LipidosisLipidosis Cholestasis (after 2-3 weeks of Rx)Cholestasis (after 2-3 weeks of Rx) Bacterial overgrowthBacterial overgrowth
Post OperativePost Operative
MultifactorialMultifactorial TransfusionsTransfusions HematomasHematomas HemolysisHemolysis SepsisSepsis TPNTPN Drugs Drugs
(anesthetics)(anesthetics)
HypoxiaHypoxia HypotensionHypotension Viral HepatitisViral Hepatitis Renal FailureRenal Failure
Post TransplantPost Transplant
Bone Marrow and Bone Marrow and Liver mostlyLiver mostly
TPNTPN DrugsDrugs ImmunosuppressivImmunosuppressiv
eses RadiationRadiation ChemotherapyChemotherapy Graft rejectionGraft rejection
Preservation injuryPreservation injury Operative Operative
complicationscomplications
Sickle Cell DiseaseSickle Cell Disease
Chronic hemolysisChronic hemolysis Hepatic dysfunctionHepatic dysfunction CirrhosisCirrhosis Secondary hemochromatosisSecondary hemochromatosis Hepatic crisisHepatic crisis
Hepatomegaly and tendernessHepatomegaly and tenderness Severe hyperbilirubinemiaSevere hyperbilirubinemia Bilirubin microliths, sludge, stones commonBilirubin microliths, sludge, stones common Obstruction rareObstruction rare
Intrahepatic Cholestasis of Intrahepatic Cholestasis of Pregnancy (IHCP)Pregnancy (IHCP)
Third TrimesterThird Trimester Possibly geneticPossibly genetic Pruritus >> cholestasis >> JaundicePruritus >> cholestasis >> Jaundice Maybe more premature/still birthsMaybe more premature/still births Distinguish from acute fatty liver Distinguish from acute fatty liver
and HELLPand HELLP
Acute Fatty Liver of Acute Fatty Liver of PregnancyPregnancy
microvesicular fatty infiltration of microvesicular fatty infiltration of hepatocyteshepatocytes
1 in 7000 to 1 in 16000 deliveries1 in 7000 to 1 in 16000 deliveries Second half of pregnancy, usually Second half of pregnancy, usually
third trimesterthird trimester Nausea, vomiting, abdominal pain, Nausea, vomiting, abdominal pain,
anorexia, and jaundice, preeclampsia anorexia, and jaundice, preeclampsia Delivery is curative (and mandatory!)Delivery is curative (and mandatory!)
HELLPHELLP
Hemolysis, Elevated Liver enzymes, Hemolysis, Elevated Liver enzymes, Low PlateletsLow Platelets
1 of 1000 pregnancies1 of 1000 pregnancies 10 to 20 percent with preeclampsia 10 to 20 percent with preeclampsia
or eclampsiaor eclampsia Diagnosed between 28 and 36 weeks Diagnosed between 28 and 36 weeks
of gestationof gestation 70 percent occurred prior to delivery 70 percent occurred prior to delivery Delivery is mandatory!Delivery is mandatory!
End Stage Liver DiseaseEnd Stage Liver Disease
Supportive CareSupportive Care TransplantTransplant
Hepatocellular InjuryHepatocellular Injury NeoplasmsNeoplasms ViralViral BacterialBacterial CongenitalCongenital ParasiticParasitic FungalFungal SystemicSystemic ImmunologicImmunologic ToxicToxic
ViralViral
Hepatitis A, B, C, D, EHepatitis A, B, C, D, E HSVHSV Hemorrhagic virusesHemorrhagic viruses AdenovirusesAdenoviruses EnterovirusesEnteroviruses
BacterialBacterial
TBTB LeptospirosisLeptospirosis SyphilisSyphilis BrucellaBrucella RickettsiaRickettsia Tropheryma WhippeliiTropheryma Whippelii RochalimeaRochalimea
CongenitalCongenital
Wilson’s disease (rare after age 40)Wilson’s disease (rare after age 40) Alpha-1-antitrypsin deficiencyAlpha-1-antitrypsin deficiency HemochromatosisHemochromatosis Porphyrias (a 24 hour urine for Porphyrias (a 24 hour urine for
porphyrins is best test to rule out all porphyrins is best test to rule out all the porphyria subtypes)the porphyria subtypes)
SystemicSystemic
Acute IschemiaAcute Ischemia Cardiac causesCardiac causes Thromboembolic diseaseThromboembolic disease TelangiectasiasTelangiectasias AmyloidAmyloid SarcoidSarcoid
ImmunologicImmunologic
Autoimmune HepatitisAutoimmune Hepatitis PBCPBC PSCPSC
DiagnosisDiagnosis HistoryHistory
Diseases/therapiesDiseases/therapies Medications/herbals/exposuresMedications/herbals/exposures Risk factors/HIV status/travel Risk factors/HIV status/travel SurgeriesSurgeries ComplicationsComplications
PhysicalPhysical Screening labsScreening labs DifferentialDifferential Further testingFurther testing
FindingsFindings Primary biliary cirrhosisPrimary biliary cirrhosis
XanthomasXanthomas Viral HepatitisViral Hepatitis
AnorexiaAnorexia MalaiseMalaise MyalgiasMyalgias
Liver failure/portal HTNLiver failure/portal HTN AscitesAscites SplenomegalySplenomegaly Spider AngiomataSpider Angiomata GynecomastiaGynecomastia
Overload FindingsOverload Findings
HyperpigmentationHyperpigmentation HemochromotosisHemochromotosis
Kayser-Fleischer ringsKayser-Fleischer rings Wilson’s diseaseWilson’s disease
LabsLabs
Transaminases – biliary or hepatic injuryTransaminases – biliary or hepatic injury Alkaline PhosphataseAlkaline Phosphatase
obstruction or intrahepatic cholestasisobstruction or intrahepatic cholestasis TBTB SarcoidSarcoid
GGT/5’-nucleotidase - biliary tract (overly GGT/5’-nucleotidase - biliary tract (overly sensitive test)sensitive test)
Prothombin timeProthombin time Correctable with vitamin K?Correctable with vitamin K?
Albumin – hepatic synthetic insufficiencyAlbumin – hepatic synthetic insufficiency
Non-obstructedNon-obstructed
Viral hepatitisViral hepatitis AMAAMA ASMA and LKMASMA and LKM Iron panel and ferritin (ferritin is an Iron panel and ferritin (ferritin is an
APR, can be elevated for multiple APR, can be elevated for multiple causes); iron saturation is keycauses); iron saturation is key
Ceruloplasmin levelCeruloplasmin level Alpha-1-antitrypsin activityAlpha-1-antitrypsin activity
Obstructed?Obstructed?
US US EUSEUS Helical CT/CTHelical CT/CT ERCP ERCP
0.2% mortality, pancreatitis 3 %0.2% mortality, pancreatitis 3 % MRCP – non-therapeutic, interpretation MRCP – non-therapeutic, interpretation
difficultdifficult Pecutaneous Transhepatic CholangiographyPecutaneous Transhepatic Cholangiography
Good for proximal lesions or if ERCP not availableGood for proximal lesions or if ERCP not available
EmergenciesEmergencies
Massive hemolysis (sepsis, malaria)Massive hemolysis (sepsis, malaria) Ascending cholangitisAscending cholangitis
FeverFever ChillsChills RUQ painRUQ pain Prior biliary surgeryPrior biliary surgery
NeonatesNeonates Fulminant hepatic failureFulminant hepatic failure
SummarySummary Many etiologies for jaundiceMany etiologies for jaundice History and physical is keyHistory and physical is key
Medical historyMedical history MedicationsMedications Risk factors Risk factors SurgeriesSurgeries
LabsLabs DifferentialDifferential Further testingFurther testing DiagnosisDiagnosis