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JaundiceJaundice

Dorota MaDorota Mańńkowska kowska --WierzbickaWierzbicka, MD, , MD, PhDPhD

Jaundice

Definition

Accumulation of yellow pigment in the

skin and other tissues (Bilirubin)

Jaundice definitionJaundice definition

�� It arises from the abnormal accumulation It arises from the abnormal accumulation of of bilirubinbilirubin in body tissues, which occurs in body tissues, which occurs when the serum when the serum bilirubinbilirubin level exceeds level exceeds 3 mg/3 mg/dLdL or 50 or 50 uumol/L.mol/L. 11 Excess Excess bilirubinbilirubincauses a yellow tinting to the skin, sclera, causes a yellow tinting to the skin, sclera, and mucous membranes. and mucous membranes.

JaundiceJaundice

� The presence of jaundice can indicate a The presence of jaundice can indicate a transient hepatitis, transient hepatitis, biliarybiliary obstruction, or obstruction, or progressive deterioration in a patient progressive deterioration in a patient awaiting liver transplantation. Thus, the awaiting liver transplantation. Thus, the appropriate management of the patient with appropriate management of the patient with jaundice depends on localizing the site and jaundice depends on localizing the site and nature of the problem. nature of the problem.

JaundiceJaundice

�� HyperbilirubinemiaHyperbilirubinemia is defined as a total is defined as a total bilirubinbilirubin level greater than 1.5 mg/level greater than 1.5 mg/dLdL , an , an unconjugatedunconjugated level greater than 1 mg/level greater than 1 mg/dLdL , or , or a conjugated a conjugated bilirubinbilirubin level greater than 0.3 level greater than 0.3 mg/mg/dLdL ..

Jaundice

JaundiceJaundice-- Causes Of Causes Of HyperbilirubinemiaHyperbilirubinemia --unconjugatedunconjugated

�� HemolysisHemolysis�� Ineffective Ineffective erythropoesiserythropoesis�� Neonatal causesNeonatal causes�� UridineUridine diphosphatediphosphateglucuronoyltransferaseglucuronoyltransferase

deficienciesdeficiencies�� Gilbert syndromeGilbert syndrome�� CriglerCrigler --NajjarNajjar syndromessyndromes

�� Miscellaneous causes (drugs, hypothyroidism, Miscellaneous causes (drugs, hypothyroidism, thyrotoxicosisthyrotoxicosis, pulmonary infarct, fasting), pulmonary infarct, fasting)

Gilbert Syndom

� Defective UDPG TransferaseUridineUridine diphosphatediphosphateglucuronoyltransferaseglucuronoyltransferase

� Usually asymptomatic� Serum BR < 3 mg%� ↑↑↑↑ BR-monoglucuronide� Benign

Crigler –Najjar Syndrome Type I

� No UDPGT� No BR conjugation� Neonatal kernicterus , death� Autosomal recessive

Crigler–Najjar Syndrom Type II

� Reduced UDPGT activity� Jaundice , 2d-3d decade of life� Mostly monoglucuronide in bile� Usually benign� Treatment: Phenobarbital, induces

more UDPGT

JaundiceJaundice-- Causes Of Causes Of HyperbilirubinemiaHyperbilirubinemia --conjugatedconjugated

�� Congenital causesCongenital causes�� Rotor syndromeRotor syndromeImpaired biliary excretion of conjugated BR. Jaundice

appearing in childhood. Autosomal recessive. Uncommon.Benign

�� DubinDubin--Johnson syndromeJohnson syndromeDefective transporter for conjugated BR. Uncommon. Benign.

Conjugated BR in blood & urine

�� CholedochalCholedochalcystscysts

�� Familial disordersFamilial disorders�� Benign recurrent Benign recurrent intrahepaticintrahepatic cholestasischolestasis�� CholestasisCholestasisof pregnancyof pregnancy

JaundiceJaundice-- Causes Of Causes Of HyperbilirubinemiaHyperbilirubinemia --conjugatedconjugated

�� HepatocellularHepatocellular defectsdefects�� Alcohol abuseAlcohol abuse�� Viral infectionViral infection

�� CholestaticCholestatic�� Primary Primary biliarybiliary cirrhosiscirrhosis�� Primary Primary sclerosingsclerosingcholangitischolangitis�� BiliaryBiliary obstructionobstruction�� Pancreatic diseasePancreatic disease

JaundiceJaundice-- Causes Of Causes Of HyperbilirubinemiaHyperbilirubinemia --conjugatedconjugated

�� Systemic diseaseSystemic disease

�� Infiltrative disordersInfiltrative disorders

�� Postoperative complicationsPostoperative complications

�� Renal diseaseRenal disease

�� SepsisSepsis

�� DrugsDrugs

JaundiceJaundice

�� UnconjugatedUnconjugatedhyperbilirubinemiahyperbilirubinemia exists if more exists if more than than 80% to 85%80% to 85% of the total of the total bilirubin bilirubin is is unconjugatedunconjugated. Conjugated . Conjugated hyperbilirubinemiahyperbilirubinemiaexists if greater than exists if greater than 30%30% of the total of the total bilirubinbilirubinlevel is conjugated. Overproduction of level is conjugated. Overproduction of bilirubinbilirubinresults in results in unconjugatedunconjugatedhyperbilirubinemiahyperbilirubinemia . Mild . Mild hyperbilirubinemiahyperbilirubinemia may require blood or urine may require blood or urine tests for detection, as jaundice usually does not tests for detection, as jaundice usually does not become apparent until the become apparent until the bilirubinbilirubin level exceeds level exceeds 3 mg/3 mg/dLdL ..

Pathophysiologic classification of Jaundice

� Hemolytic Jaundice

� Hepatic Jaundice

� Obstructive Jaundice

Hemolytic Jaundice

PathogenesisOverproduction

� Hemolysis (intra and extra vascular)� inherited or genetic disorders� acquired immune hemolytic anemia

(Autoimmune hemolytic anemia)� nonimmune hemolytic anemia

(paroxysmal nocturna Hemoglobinruia)

� Ineffective erythropoesis

Overproduction may overload the liver with UB

Hemolytic Jaundice

Symptomsweakness, Dark urine, anemia,

Icterus, splenomegaly

Lab� UB↑↑↑↑ without bilirubinuria� fecal and urine urobilinogen↑↑↑↑� hemolytic anemia� hemoglobinuria (in acute intravascular hemolysis)

� Reticulocyte counts↑↑↑↑

Hepatic Jaundice

Due to a disease affective hepatic tissue either congenital or acquired diffuse hepatocellular injury

Hepatic Jaundice

Pathogenesis

� Impaired or absent hepatic conjugation of bilirubin� decreased GT activity (Gilbert‘s syndrome)� hereditary absence or deficiency of UDPGT (Grigler-Najjar

Syndrome)

� Familiar or hereditary disorders� Dubin-Johnson Syndrome� Rotor syndrome

• Acquired disorders� hepatocellular necrosis� intrahepatic cholestasis

(Hepatitis, Cirrhosis, Drug-related)

HepatocellularHepatocellular defectsdefects

�� Viral hepatitisViral hepatitis�� Hepatitis A Hepatitis A

�� Hepatitis BHepatitis B

�� Hepatitis CHepatitis C

�� Hepatitis DHepatitis D

�� Hepatitis EHepatitis E

�� Hepatitis GHepatitis G

HepatocellularHepatocellular defectsdefects

�� Alcohol abuseAlcohol abuse�� Liver Liver steatosesteatose(fatty liver)(fatty liver)

�� HepatitisHepatitis

�� Cirrhosis of the liverCirrhosis of the liver

Obstructive Jaundice

Pathogenesis� it is due to intra- and extra hepatic obstruction

of bile ducts

� intrahepatic Jaundice: Hepatitis, PBC, Drugs

� Extra Hepatic Biliary Obstruction: Stones, Stricture, Inflammation, Tumors, (Ampulla of Vater)

CholestasisCholestasis

�� PBCPBC

�� PSCPSC

�� BiliaryBiliary obstructionobstruction

�� Pancreatic diseasePancreatic disease

PBCPBC

� The clinical features include jaundice, pruritus, steatorrhea, xanthomas, and osteopenia. In advanced disease, signs of portal hypertension will occur with esophageal varices, ascites, and other conditions.

� Primary biliary cirrhosis is a chronic progressive cholestatic disorder typically, although not exclusively, found in women in the fourth to fifth decade of life.

PBCPBC

�� laboratory abnormalities: laboratory abnormalities: �� a characteristic isolated alkaline a characteristic isolated alkaline phosphatasephosphatase

elevation out of proportion to other liver elevation out of proportion to other liver function tests, function tests,

�� Elevated Elevated �� serum serum IgMIgM , ,

�� cholesterol, cholesterol,

�� antimitochondrialantimitochondrial antibody (AMA) .antibody (AMA) .

PBCPBC

�� laboratory abnormalities: laboratory abnormalities: �� a characteristic isolated alkaline a characteristic isolated alkaline phosphatasephosphatase

elevation out of proportion to other liver elevation out of proportion to other liver function tests, function tests,

�� Elevated Elevated �� serum serum IgMIgM , ,

�� cholesterol, cholesterol,

�� antimitochondrialantimitochondrial antibody (AMA) .antibody (AMA) .

PSCPSC

� Progressive cholestatic liver disease, which is found mostly in men of middle age.

� Inflammation of both intrahepatic and extrahepatic bile ducts

� Clinically, patients present with recurrent abdominal pain, fever, and intermittent jaundice and later with symptoms of portal hypertension.

� Characteristic narrowing or "beading" occurs in the hepatic ducts, as demonstrated by cholangiogram.

PSC vs. UCPSC vs. UC

�� Chronic inflammatory bowel diseases, such Chronic inflammatory bowel diseases, such as ulcerative colitisas ulcerative colitisoror CrohnCrohn , are , are associated in 30% to 75% of primary associated in 30% to 75% of primary sclerosingsclerosingcholangitischolangitis patientspatients

�� Of all patients with ulcerative colitis, 5% to Of all patients with ulcerative colitis, 5% to 10% will have primary 10% will have primary sclerosingsclerosingcholangitischolangitis..

Obstructive Jaundice

symptoms

� Pruritus

� Jaundice may vary in intensity

� Chill+fever+gall bladder enlargement

→→→→stone+cholangitis

Obstructive JaundiceLab Findings

� Serum Bilirubin ↑↑↑↑� Feceal urobilinogen↓↓↓↓ (incomplete obstruction)� Feceal urobilinogen absence (complete

obstruction)� urobilinogenuria is absent in complete

obstructive jaundice� bilirubinuria ↑↑↑↑� ALP ↑↑↑↑ , GGTP ↑↑↑↑� cholesterol ↑↑↑↑

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� The investigation of a patient with jaundice The investigation of a patient with jaundice begins with a thorough review of the history begins with a thorough review of the history of presentation, medication use, past of presentation, medication use, past medical history, physical examination, and medical history, physical examination, and evaluation of liver function tests. evaluation of liver function tests.

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

� Several questions must be answered initially: � 1. Is the elevated bilirubin conjugated or unconjugated? In

general, most jaundiced patients will not have an isolated unconjugated hyperbilirubinemia.

� 2. If the hyperbilirubinemia is unconjugated, is it caused by increased production, decreased uptake, or impaired conjugation?

� 3. If the hyperbilirubinemia is conjugated, is the problem intrahepatic or extrahepatic?

� 4. Is the process acute or chronic?

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� Patients with conjugated Patients with conjugated hyperbilirubinemiahyperbilirubinemiausually have acquired diseaseusually have acquired disease-- identify an identify an intrahepaticintrahepatic or an obstructive cause.or an obstructive cause.

�� Acute disease usually can be differentiated from Acute disease usually can be differentiated from chronic disease by the patient's history, physical chronic disease by the patient's history, physical examination (examination (xanthelasmaxanthelasma, spider , spider angiomaangioma, , ascitesascites, or , or hepatosplenomegalyhepatosplenomegaly), and laboratory ), and laboratory tests (tests (hypoalbuminemiahypoalbuminemia,, thrombocytopeniathrombocytopenia, and , and an uncorrectable prolongation of the an uncorrectable prolongation of the prothrombinprothrombintime).time).

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� Chronic Chronic cholestasischolestasismay arise from such may arise from such diseases as cirrhosis, primary diseases as cirrhosis, primary sclerosingsclerosingcholangitischolangitis, primary , primary biliarybiliary cirrhosis, cirrhosis, secondary secondary biliarybiliary cirrhosis, or carcinoma or cirrhosis, or carcinoma or from drugs.from drugs.

�� Patients with chronic Patients with chronic cholestasischolestasisusually do usually do not have hepatitis or gallstones.not have hepatitis or gallstones.

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� The presence of fever, right upper quadrant The presence of fever, right upper quadrant pain, tenderness,pain, tenderness,hepatomegalyhepatomegaly, and new, and new--onsetonsetbilirubinuriabilirubinuria usually indicates acute usually indicates acute disease.disease.

�� Patients older than 50 years of age withPatients older than 50 years of age withasymptomatic cholestasisasymptomatic cholestasisand mildand mildhepatomegalyhepatomegalymay have carcinoma of the may have carcinoma of the pancreas orpancreas orbiliarybiliary tree.tree.

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� Women aged over 30 years of age are more Women aged over 30 years of age are more likely to have likely to have choledocholithiasischoledocholithiasis..

Gallstones

� cholelithiasis� the formation or

presence of stones in the gallbladder or common bile duct. chole = bile, lith = stone, iasis = condition

Gallstones

� biliary colic: pain associated with gallstones that have entered the common bile duct.

� choledocholithiasis the presence of gallstones in the common bile duct.

� cholecystitisinflammation of the gallbladder.� cholangitis inflammation of the bile ducts.� cholecystectomy: surgical removal of the gallbladder.

Gallbladder DisordersGallbladder Disorders

Risk factors for Risk factors for cholelithiasischolelithiasis� a. Age � b. Family history, also Native Americans and

persons of northern European heritage� c. Obesity, hyperlipidemia� d. Females, use of oral contraceptives� e. Conditions which lead to biliary stasis:

pregnancy, fasting, prolonged parenteral nutrition� f. Diseases including cirrhosis, ileal disease or

resection, sickle-cell anemia, glucose intolerance

Gallbladder DisordersGallbladder Disorders

Manifestations of cholelithiasis� a. Many persons are asymptomatic� b. Early symptoms are epigastic fullness after meals or

mild distress after eating a fatty meal� c. Biliary colic (if stone is blocking cystic or common bile

duct): steady pain in epigastric or RUQ of abdomen lasting up to 5 hours with nausea and vomiting

� d. Jaundice may occur if there is obstruction of common bile duct

Gallbladder DisordersGallbladder Disorders

Manifestations of acute cholecystitis� a. Episode of biliary colic involving RUQ

pain radiating to back, right scapula, or shoulder; the pain may be aggravated by movement, or deep breathing and may last 12 – 18 hours

� b. Anorexia, nausea, and vomiting� c. Fever with chills

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� An adult withAn adult with asymptomaticasymptomatic, isolated , isolated unconjugatedunconjugatedhyperbilirubinemiahyperbilirubinemia who is who is not taking any drugs and has no evidence of not taking any drugs and has no evidence of hemolysishemolysisprobably has Gilbert syndrome probably has Gilbert syndrome and can be monitored with and can be monitored with bilirubinbilirubindeterminations for 12 months. If no determinations for 12 months. If no abnormality develops, no further evaluation abnormality develops, no further evaluation is needed.is needed.

Evaluation to the patient with jaundiceEvaluation to the patient with jaundice

�� Fever, Fever, leukocytosisleukocytosis, and, and hypotensionhypotensionpoint point to ascending to ascending cholangitischolangitis

�� AsterixisAsterixis, confusion, or stupor may indicate , confusion, or stupor may indicate severe severe hepatocellularhepatocellular dysfunction or dysfunction or fulminantfulminant hepatocellularhepatocellular failure failure

Clinical symptomsClinical symptoms

�� FeverFever

�� ChillsChills

�� Weight lossWeight loss

�� Flu like symptomsFlu like symptoms

�� Abdominal painAbdominal pain

�� AnorexiaAnorexia

�� Nausea, and vomiting Nausea, and vomiting

�� PruritusPruritus

Physical examinationPhysical examination

� General appearance � cachexia, muscle wasting, palmar erythema,

Dupuytren contracture, abnormal nails, parotid enlargement, or xanthelasmas, gynecomastia, spider nevi, or dilated veins.

Physical examinationPhysical examination

� The size and consistency of the liver � shrunken, nodular liver - cirrhosis, � a palpable mass - an abscess or malignancy. � If the liver span is greater than 15 cm- fatty infiltration,

congestion, other infiltrative diseases, or malignancy. � Liver tenderness may denote acute disease but is

generally not helpful. � The presence of a friction rub or bruit suggests

malignancy.

Clinical examinationClinical examination

� Spider angioma, palmar erythema, and distended abdominal veins

� Ascites in the presence of jaundice (cirrhosis, malignancy and severe acute disease, such as viral or alcoholic hepatitis)

� Splenomegaly (infections, infiltrative diseases, viral hepatitis, or cirrhosis)

� A palpable, distended gallbladder suggests malignant biliaryobstruction.

� Asterixis in fulminant hepatic failure and end-stage liver disease.

� Patients with biliary colic or infection may have fever.

Laboratory testsLaboratory tests

�� TB (conjugated, TB (conjugated, unconjugatedunconjugated))

�� AspATAspAT, , AlATAlAT

�� GGTPGGTP

�� APAP

�� TP + (albumin, TP + (albumin, gammaglobulingammaglobulin))

�� ProthrombinProthrombin

Laboratory testsLaboratory tests

�� TChTCh�� AMAAMA�� 55’’ --NTNT�� LAPLAP�� Alfa1Alfa1--antitrypsinantitrypsin�� Iron levelsIron levels�� CeruloplasminCeruloplasmin�� AlfaAlfa --fetoproteinfetoprotein (AFP)(AFP)�� Antinuclear antibodyAntinuclear antibody

Noninvasive testsNoninvasive tests

�� USUS�� CTCT�� RadionuclideRadionuclide imagingimaging is an excellent means is an excellent means

of detecting cystic duct obstruction. It is the of detecting cystic duct obstruction. It is the test of choice if acute test of choice if acute cholecystitischolecystitisis is suspected, but it has little value in suspected, but it has little value in differentiating differentiating intrahepaticintrahepatic from from extrahepaticextrahepatic causes of causes of cholestasischolestasis..

Invasive testsInvasive tests

�� ERCP ERCP -- endoscopicendoscopicretrograde retrograde cholangiopancreatographycholangiopancreatography

�� PTC PTC -- percutaneouspercutaneoustranshepatictranshepaticcholangiographycholangiography

�� liver biopsyliver biopsy

ERCPERCP

�� ERCP is 90% successful regardless of the ERCP is 90% successful regardless of the presence or absence of presence or absence of ductalductaldilation and can dilation and can localize the site of obstruction in more than localize the site of obstruction in more than 90% of patients. It is particularly helpful in 90% of patients. It is particularly helpful in diagnosing patients with common duct stones. diagnosing patients with common duct stones. Because it has therapeutic capabilities, it Because it has therapeutic capabilities, it allows some patients to avoid surgery. ERCP allows some patients to avoid surgery. ERCP is also helpful if a stricture due to chronic is also helpful if a stricture due to chronic pancreatitispancreatitisis suspected. is suspected.

PTCPTC

� PTC visualizes the biliary tree in 90% to 100% of patients with dilated ducts and localizes the site of obstruction in 90% of cases. It locates the obstruction in 50% to 90% of patients without dilated ducts, as determined by ultrasound. PTC is less expensive than ERCP and often is easier to perform. The patient must have a prothrombintime of less than 16 seconds,a platelet count greater than 50,000, and no ascites. Minor complications occur in 30% of patients. Major complications, including sepsis, bleeding, biliary leak, pneumothorax, arteriovenousfistula, hematoma, abscess, and peritonitis, occur in 1% to 10% of patients who undergo PTC.