Jaundice Definition Accumulation of yellow pigment in the skin and other tissues (Bilirubin)

Jaundice

Definition

Accumulation of yellow pigment in t

he skin and other tissues (Bilirubin)

Bilirubin Metabolism Bilirubin formation

Transport of bilirubin in plasma

Hepatic bilirubin transport Hepatic uptake

Conjugation

Biliary excretion

Enterohepatic circulation

Bilirubin

RBCs Senecent RBCsIronhemoglobinGlobin

Bilirubin Biliverdin heme

Hepatic Hemoproteins nonhemoglobin hemenonhemoglobin hemoprotein

Premature destruction of newly formed RBCs

CMHO

RCBR

1-5%

Chiefly70+%

20%

Bilirubin formation

120ds

Transport of Bilirubin in Plasma

Albumin + UB UB ~ Albumin Complex

MolarRatio

Bilirubin

Bilirubin

Plasma proteinAlbumin

H affinity binding sites

L affinity binding sites

can be replaced byOther organic anions

PH UB

2:1

>2:1

CB

1. Hepatic uptake of BilirubinUCB~Albumin Complex Separated

Bilirubin Plasma membrane of the liver(be) taken upMTA (receptor ?)

Transfer across

Microvillar membrane

3.Biliary Excretion of Bilirubin

Bile canaliculus

2.Conjugation of Bilirubin

UCB carrier protein ER

CBGACB

(be) bound to transfer

Conjugation(catalized by UDPGT)

Z protein

ligation (Y protein)

Hepatic Bilirubin Transport

(lipid soluble)

(water soluble)

• UDPGT: Uridine Diphosphate Glucuronyl

Transferase

• UCB: because of its tight albumin binding

and lipid solubility, it is not excreted in uri

ne.

• CB: is less tightly bound to albumin and is

water soluble, so it is filtered at the glomer

ulus and appears in the urine.

Entero-hepatic circulation

CB B and I Urobilinogens (coloress) be degradedBacterial Enzymes

feces (feceal urobilinogens)

Reabsorbed plasma

circulation kidneys

50-200 mg/dmostly

urine urobilinogen4 mg/d

T

liver Bile fecesre-excreted excreted

90%

trace

20%

•The serum of normal adults contains 1 mg of bilirubin per 100 ml.

•In healthy adults The direct fraction is usually <0.2 mg/100 mlThe indirect fraction is usually <0.8 mg/100 ml

Pathophysiologic classification of Jaundice

Hemolytic Jaundice

Hepatic Jaundice

Obstructive Jaundice(Cholestasis)

Congenital Jaundice

Jaundice classification

predominantly unconjugated hyperbilirubinaemia

predominantly conjugated hyperbilirubinaemia

Hemolytic Jaundice Pathogenesis

OverproductionHemolysis (intra and extra vascular)

inherited or genetic disorders acquired immune hemolytic anemia

(Autoimmune hemolytic anemia) nonimmune hemolytic anemia

(paroxysmal nocturna Hemoglobinruia)

Ineffective erythropoiesis

Overproduction may overload the liver with UB

Hemolytic JaundiceSymptoms weakness, Dark urine, anemia,

Icterus, splenomegaly

Lab UB without bilirubinuria fecal and urine urobilinogen hemolytic anemia hemoglobinuria (in acute intravascular hemol

ysis) Reticulocyte counts

Hemolytic Jaundice (pre-hepatic)

Serum / blood: • bilirubin (micormoles/l) 50-150; normal rang

e 3-17 • AST I.U. < 35; normal range <35 • ALP I.U. <250; normal range <250 • gamma GT I.U. 15-40; normal range 15-40 • albumin g/l 40-50; normal range 40-50 • reticulocytes(%) 10-30; normal range <1 • prothrombin time (seconds) 13-15; normal r

ange 13-15

Hemolytic Jaundice (pre-hepatic)

urinary changes: • bilirubin: absent • urobilinogen: increased or norm

alfaecal changes: stercobilinogen: normal

Obstructive Jaundice

Pathogenesisit 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)

Etiology of Obstructive Jaundice

Intrahepatic-Liver cell Damage/Blockage of Bile Canaliculi

• Drugs or chemical toxins• Dubin-Johnson syndrome• Estrogens or Pregnancy• Hepatitis-viral,chemical• Infiltrative tumors• Intrahepatic biliary hypoplasia or atresia• Primary biliary cirrhosis

Etiology of Obstructive Jaundice

Extrahepatic-Obstructive of bile Ducts

• Compression obstruction from tumors

• Congenital choledochal cyst

• Extrahepatic biliary atresia

• Intraluminal gallstones

• Stenosis-postoperative or inflammary

cholestasisclinical features

• pain, due to gallbladder disease, malignancy, or stretching of the liver capsule

• fever, due to ascending cholangitis

• palpable and / or tender gallbladder

• enlarged liver, usually smooth

General signs of cholestasis• xanthomas: palmar creases, below the brea

st, on the neck. They indicate raised serum cholesterol of several months. Xanthomas on the tendon sheaths are uncommonly associated with cholestasis.

• xanthelasma on the eyelids • scratch marks: excoriation • finger clubbing • loose, pale, bulky, offensive stools • dark orange urine

Obstructive Jaundice Lab Findings• Serum Bilirubin• Feceal urobilinogen (incomplete obstruction)• Feceal urobilinogen absence (complete obstructi

on)• urobilinogenuria is absent in complete obstructi

ve jaundice• bilirubinuria • ALP • cholesterol

Obstructive Jaundiceextrahepatic

serum / blood • bilirubin (micromoles/l) 100-500; normal ran

ge 3-17 • AST I.U. 35-400; normal range <35 • ALP I.U. >500; normal range <250 • gamma GT I.U. 30-50; normal range 15-40 • albumin g/l 30-50; normal range 40-50 • reticulocytes(%) <1; normal range <1 • prothrombin time (secs) 15-45; normal rang

e 13-15 • ( " + parenteral vitamin K) falls

Obstructive Jaundiceextrahepatic

urinary changes • bilirubin: increased • urobilinogen: reduced or absent

faecal changes stercobilinogen: reduced or absent

Hepatic Jaundice

Due to a disease affective hepatic ti

ssue 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)

Gross specimen of cirrhosis of the liver

Hepatic Jaundice

Symptoms

weakness, loss appetite, hepatomegaly, palmar eryth

ema, spider

Lab Findings

• liver function tests are abnormal

• both CB and UCB

• Bilirubinuria

Hepatic Jaundiceserum / blood

• bilirubin (micromoles/l) 50-250; normal range 3-17

• AST I.U. 300-3000; normal range <35 • ALP I.U. <250-700; normal range <250 • gamma GT I.U. 15-200; normal range 15-40 • albumin g/l 20-50; normal range 40-50 • reticulocytes(%) <1; normal range <1 • prothrombin time (secs) 15-45; normal rang

e 13-15 • ( " + parenteral vit. K) 15-45

Hepatic Jaundice

urinary changes • bilirubin: normal or increased • urobilinogen: normal or reduced

faecal changes stercobilinogen: normal or reduced

Jaundicediagnosis(1)

history and examinationurine, stoolsserum biochemistry • bilirubin • transaminases - AST, ALT • albumin • alkaline phosphatase

Jaundicediagnosis(2)

haematology• haemoglobin • WCC • platelets • prothrombin time +/- parenteral vitamin Kabdominal ultrasound and chest X-rayfurther investigations - determined by the

basis of the jaundice, e.g. pre-hepatic, hepatic, extra-hepatic

conjugated hyperbilirubinaemia

the liver is able to conjugate bilirubin, but the excretion is impaired.

failure of bilirubin excretion by hepatocytes:

• Dubin-Johnson syndrome • Rotor's syndromeobstruction to biliary flow i.e. cholestasis, b

oth intra-hepatic and extra-hepatic

The proportion of conjugated bilirubin to the total raised bilirubin

• 20-40% of total: more suggestive of hepatic than posthepatic jaundice

• 40-60% of total: occurs in either hepatic or posthepatic causes

• > 50% of total: more suggestive of posthepatic than hepatic jaundice

• less than 20% :secondary to haemolysis or constitutional e.g. Gilbert's disease, Crigler-Najjar syndrome

unconjugated hyperbilirubinaemia

• increased bilirubin formation• failure of bilirubin uptake(Gilber

t's disease)• failure of bilirubin conjugation

unconjugated hyperbilirubinaemia increased bilirubin formation

haemolysis ineffective erythropoiesis: • megaloblastic anaemia • iron deficiency • haemoglobinopathies

unconjugated hyperbilirubinaemia failure of bilirubin conjugation

• neonatal jaundice • Crigler Najjar syndrome • drug inhibition e.g. chloramphen

icol • extensive hepatocellular disease

e.g. hepatitis, cirrhosis

Cholestasisdiagnosis

• elevated serum bilirubin - in proportion to duration of cholestasis; returns to normal once cholestasis is relieved

• raised serum alkaline phosphatase - to more than 3X upper limit of normal;

• LFTs - aminotransferases mildly raised; raised gamma GT

• increased urinary bilirubin • urinary urinobilinogen is excreted in proporti

on to amount of bile reaching the duodenum i.e. absence of urinobilinogen indicates complete biliary obstruction

Identification of cause

• dilated ducts on ultrasound - percutaneous transhepatic cholangiograpy

• undilated ducts on ultrasound - endoscopic retrograde cholangio-pancreatography

• needle biopsy of the liver

Hepatocellular carcinoma

Primary sclerosing cholangitis in childhood

Accompanied Symptoms

• Fever

• Pain,Charcot syndrome

• Hepatomegaly

• Spleenmegaly

• Ascites

• GI bleeding

• itch

Jaundice- Differential diagnosis

1. Once Jaundice is recognized, it is important to det

ermine whether hyperbilirubinemia is predominantly CB or UCB?

2. Differentiation of hemolitic from other type of Jaundice is usually not difficult.

3. The laboratory findings are in constant in partial biliary obstruction and differentiation from intrahepatic cholestesis is particularly difficult.

Jaundice- Differential diagnosis

Differential Diagnosis

UCB or CB Exclude UCB (e.g. hemolysis or Gilbert Synd.) Distinguish hepatocellular from obstructive Distinguish intrahepatic from extra hepatic chol

estasis

Case Study1• History: 68-year-old,jaundice,stomach pain, “dark urine”,itching of the skin,rapid weight loss of 21lb• Lab data CBC within narmal limitsTotal bilirubin:238μmol/lGGT:300U/lALP:360U/lAST:80u/lALT:75u/lUrinalysis:positive bilirubin,normal urobilinogenSerum amylase:elevated

Case Study1

Question:

• What is the most probable diagnosis for this patient?

• Which labtory tests provided the most information,and which provided the least?

Case Study2

• History:38-year-old white

female,jaundice,right upper

quadrant abdominal

pain,nausea,vomiting,itching

skin.She has a history of

intravenous drug use and alcohol

abuse.

Case Study2

• Lab data elevated total bilirubin(136 μmol/l) elevated conjugated bilirubin(102μmol/l)Urine:orange-brown,3+bilirubin,normal urobilino

gen elevated ALP(1.5ULT),GGT(3ULT),ALT,AST(5

ULT) Modest increase:Serum cholesterol and triglycerid

e

Case Study2

Question• What is the probable diagnosis for this

patient?Why?

• What other laboratory test would recommend to confirm this diagnosis?

• Which laboratory tests ordered provided the most information?Why?

SUMMARY

• Have the patient had an isolated elevation of serum bilirubin?

SUMMARY

• Is the bilirubin elevation due to an increased unconjucated or conjucated fraction?

SUMMARY

• Is the hyperbilirubinemia hepatocellular or cholestatic?

SUMMARY

• If cholestatic,is it intra-or extrahepatic?