JAUNDICE

MARYAM JAMILAH BINTI ABDUL HAMID

082013100002

IMS BANGALORE

LEARNING OUTCOME

• Definition

• Clinical examination

• Classification

• Etiology

• Pathogenesis

DEFINITION

A yellowish discoloration of tissue

resulting from the deposition of bilirubin

Also known as icterus

Clinical jaundice when serum bilirubin level >2 mg/dl

CLINICAL EXAMINATION

1. Sclera

2. Conjunctiva

3. Underneath the tongue

4. Skin

What is bilirubin?

• Tetrapyrrole pigment, 250-300 mg/day produced

• Source: End product of heme degradation

– Senescent erythrocyte (70-80%)

– Prematurely destroyed erythroid cells in bone marrow

– Turnover of hemoproteins; myoglobin & cytochromes formed in tissues throughout the body

What is bilirubin? (cont.)• Normal values & types:-

– Total serum bilirubin: <1 mg/dl

– Conjugated/direct bilirubin; 0.1-0.3 mg/dl

– Unconjugated/indirect bilirubin; 0.2-0.7 mg/dl

• Formation:-– In reticuloendothelial cells; spleen & liver

1. Microsomal enzyme; heme oxygenase

Cleaves α bridge of the porphyrin group & opens the heme ring

End-product: biliverdin, carbon monoxide, iron

2. Cytosolic enzyme; biliverdin reductase

Reduces central methylene bridge of biliverdin

End-product: bilirubin

3. Unconjugated bilirubin bound to albumin is taken up by hepatocytes via a process that at least partly involves carrier-mediated membrane transport

4. In hepatocytes, unconjugated bilirubin is bound in the cytosol to a number of proteins including proteins in the glutathione-S-transferasesuperfamily. Protein decrease efflux of bilirubin back into serum and present bilirubin for conjugation

5. In endoplasmic reticulum, bilirubin is solubilized by conjugation to glucuronic acid, a process that disrupts the internal H-bonds & yields bilirubin monoglucoronide & diglucoronide; Uridinediphosphate-glucuronosyltransferase (UDPGT)

6. Diffuse from endoplasmic reticulum to canalicularmembrane bileduodenum proximal small intestine distal ileum & colon hydrolyzed to unconjugated bilirubin by β glucuronidasesreduced by normal gut bacteria & form colourless tetrapyrroles(urobilinogens)

7. A) 80-90%of urobilinogens excreted in feces either unchanged or into urobilins

B) 10-20% urobilinogensenters enterohepaticcirculation and re-excreted by liver

*however, <3 mg/dl escapes hepatic uptakes and filter across the renal glomerulus & excreted in urine

Bilirubin should be balanced !

• Balance between input from production of bilirubin and hepatic/biliary removal of the pigment in normal person

• Causes of hyperbilirubinemiaa) Overproduction of bilirubin

b) Impaired uptake, conjugation, or excretion of bilirubin

c) Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts

Increase unconjugated bilirubin

Overproduction

Impairment of uptake

Defect conjugation of bilirubin

Increase conjugated bilirubin

Decrease excretion into the bile ductile

Backward leakage of the pigment

PREHEPATIC JAUNDICEUNCONJUGATED

HYPERBILIRUBINEMIA

A)HEMOLYTIC DISEASE1. Inherited

i. Spherocytosis, elliptocytosis, G6PD, Pyruvate kinase

ii. Sickle cell anemia

2. Acquiredi. Microangiopathic hemolytic

anemia

ii. Spur cell anemia

iii. Paroxysmal nocturnal hemoglobinuria

iv. Immune hemolysis

v. Parasitic infection; malaria, babesiosis

B) INEFFECTIVE ERYTHROPOIESIS

1. Cobalamin, folate,irondeficiencies

2. Thalassemia

C)DRUGS1. Rifampicin, probenecid,

ribavirin

D)INHERITED CONDITIONS

1. Crigler-Najjar type I & II2. Gilbert’s syndrome

CONJUGATED HYPERBILIRUBINEMIA

A)INHERITED CONDITIONS1. Dubin-Johnson syndrome

2. Rotor’s syndrome

PREHEPATIC JAUNDICE

DUBIN-JOHNSON SYNDROME

• Autosomal recessive trait

• Defect excretion of conjugated bilirubin so increase conjugated bilirubin

• Defect ATP-dependent organic anion transport in bile canaliculi ; mutation of MRP-2 protein

• Black liver jaundice

CRIGLER-NAJJAR

• Defect in conjugation

Type 1 (congenital non-hemolytic jaundice)

Deficiency of UDP glucuronyltransferase

Jaundice appears within 24 hr after birth, kernicterus

Fatal; die within 2 years old

Type 2

Milder form

GILBERT’S SYNDROME

• Autosomal dominant

• Defect uptake of bilirubin by liver

• 3 mg/dl serum bilirubin, mild jaundice

Black liver jaundice seen in Dubin-Johnson

syndrome

Phototheraphy

HEPATIC JAUNDICEVIRAL HEPATITIS

a) Hepatitis virus; HAV, HBV, HCV, HDV, HEV

b) Epstein-Barr virus

c) Cytomegalovirus

d) Herpes simplex virus

ALCOHOL

WILSON’S DISEASE

AUTOIMMUNE HEPATITIS

DRUG TOXICITYa) Predict/dose

dependent; paracetamol

b) Unpredictable/ idiosyncratic; isoniazid, chloramphenicol

ENVIRONMENTAL TOXINSa) Vinyl chlorideb) Jamaica bush teac) Wild mushroom

Hepatitis B, Hepatitis C, Hepatitis D

Alcohol Liver DiseaseExcessive intake of alcohol; everydayStages:-

1. MINIMAL CHANGE, OR FATTY LIVER

• not linked to deterioration in liver function

• liver function tests (LFT); abnormal

• Fatty liver is reversible with abstinence from alcohol

2. ALCOHOLIC HEPATITIS

• mild to life threatening

• LFTs will almost always be abnormal

• may develop jaundice

• abstinence from alcohol can reverse the effects

• continue to drink heavily lead to cirrhosis

3. CIRRHOSIS

• irreversible stage of ALD

• scarring of the liver and development of liver nodules

• severely affects liver function and reduces life expectancy

• LFT abnormal

• Jaundice, bruising or bleeding

• Can lead to decompensated ALD

Wilson’s disease• Rare autosomal recessive inherited disorder of

copper metabolism

• Excessive deposition of copper in the liver, brain, and other tissues

• Often fatal if not recognized and treated when symptomatic

Kayser-Fleischer RingRhodanine stain (specific for copper)

OBSTRUCTIVE JAUNDICEINTRAHEPATIC

A. Viral hepatitis Fibrosing cholestatic hepatitis

(HBV,HBC)

HAV, EBV CMV

B. Alcoholic hepatitis

C. Drug toxicity Pure cholestasis; anabolic &

contraceptive steroids

Cholestatic hepatitis; erythromycin estolate,chlorpromazine

Chr. Cholestasis; chlorpromazine, prochlorperazine

D. Primary biliary cirrhosisE. Primary sclerosing

cholangitisF. Vanishing bile duct syndromeG. InheritesH. Cholestasis of pregnancyI. Total parental nutritionJ. Nonhepatobiliary sepsisK. Benign postoperative

cholestasisL. Paraneoplastic syndromeM. Venoocclusive diseaseN. Graft-vs-host diseaseO. Infiltrative disease; TB,

lymphoma, amyloidP. Infections; malaria,

leptospirosis

EXTRAHEPATIC

A) MALIGNANT

• Cholangiocarcinoma

• Pancreatic cancer (head)

• Gallbladder cancer

• Ampullary cancer

• Malignant involvement of the porta hepatis lymph nodes

B) BENIGN• Cholelithiasis• Choledocholithiasis• Postoperative biliary

structure• Primary sclerosing

cholangitis• Chr. Pancreatitis• AIDS cholangiopathy• Mirizzi’s syndrome• Parasitic disease;

ascariasis

Cholelithiasis• 10% to 20% in Western countries & Northern Hemisphere,

20% to 40% in Latin American countries, 3% to 4% in Asian countries

• Cholesterol and Pigment stones insoluble calcium bilirubinate salts

• Unconjugated bilirubin in the biliary tree

Factors:

• Demography: Asian more than Western, rural more than urban

• Chronic hemolysis (e.g., sickle cell anemia, hereditary spherocytosis)

• Biliary infection

• Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

BLACK PIGMENT STONE BROWN PIGMENT STONE

In sterile gallbladder bileIn infected intrahepatic or

extrahepatic ducts

Small, fragile to touch and numerous

Soft, greasy, soaplikeconsistency

Radiopaque Radiolucent

Choledocholithiasis

• Stones within the biliary tree

• Obstructions to the flow of bile

• In Western nations, almost all stones are derived from the gallbladder

• In Asia, incidence of primary ductaland intrahepatic (usually pigmented stone formation) is more higher

• Factors: Bile stasis, bactibilia, chemical imbalances, pH imbalances, increased bilirubin excretion and the formation of sludge

Pancreatic carcinoma

• Location: head of pancrease

• Causing obstruction of the common bile duct and pancreatic duct

• Obstruction jaundice

REFERENCES

• Robbins Pathology 9th edition

• Harrison’s Internal Medicine 18th Edition

• http://www.netdoctor.co.uk/diseases/facts/alcliver.htm

• http://imgarcade.com/1/pigment-gallstones/