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