Jaundice

Definition

Accumulation of yellow pigment in

the 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

urine.

• CB: is less tightly bound to albumin and is

water soluble, so it is filtered at the

glomerulus 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

hemolysis) Reticulocyte counts

Hemolytic Jaundice (pre-hepatic)

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

range 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 range 13-15

Hemolytic Jaundice (pre-hepatic)

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

normalfaecal 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 breast, 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

obstruction)• urobilinogenuria is absent in complete

obstructive jaundice• bilirubinuria • ALP • cholesterol

Obstructive Jaundiceextrahepatic

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

faecal changes stercobilinogen: reduced or

absent

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)

Hepatic Jaundice

Symptoms

weakness, loss appetite, hepatomegaly, palmar

erythema, 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

range 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,

both 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(Gilbert'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.

chloramphenicol • extensive hepatocellular

disease e.g. hepatitis, cirrhosis

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

urobilinogen elevated

ALP(1.5ULT),GGT(3ULT),ALT,AST(5ULT) Modest increase:Serum cholesterol and

triglyceride

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?