JAUNDICE

Vineela Nekkanti V Pharm.D

Contents of the topic

Definition

Classification

Signs and symptoms

Diagnosis

Pathophysiology

Prevention

Treatment

Definition :

Jaundice, as in the French jaune, refers to the yellow discoloration of the skin.

Also known as Icterus

Jaundice is a liver disease characterized by elevated levels of bilirubin in the blood termed as hyperbilirubinaemia.

Normal range of serum bilirubin concentration is 0.3-1.3mg/dl

Jaundice occurs when bilirubin levels exceeds 2mg/dl

Introduction to Bilirubin :

Bilirubin is a orange-yellow pigment formed

in the liver by the breakdown of

hemoglobin and excreted in bile.

Two types of bilirubin :

Conjugated and Unconjugated bilirubin

Sources of Bilirubin :

• Catabolism of heme of hemoglobin (80-

85%)

• Non-hemoglobin heme containing

pigments such as myoglobin, catalase

and cytochromes

Conjugated Bilirubin

Unconjugated Bilirubin

Water soluble Water Insoluble

It reacts quickly to produce azobilirubin

It reacts slowly to produce azobilirubin

It produces azobilirubin only in the presence of

dye

It produces azobilirubin in the absence of dye

Known by Direct bilirubin Known by Indirect bilirubin

Metabolism of Bilirubin

Types of Jaundice

Prehepatic Jaundice

Intrahepatic jaundice

Post hepatic Jaundice

Type of Jaundice

Pre-Hepatic

Intra-hepatic

Post-Hepatic

Other Name Hemolytic jaundice

Hepatocellular Jaundice

Obstructive/Regurgitation

Jaundice

Cause Increased hemolysis of erythrocytes

Dysfunction of liver due to damage to

parenchymal cells

Obstruction of bile duct –

prevents the passage of bile into intestine

Examples Malaria, sickle cell anemia, incompatible

blood transfusion

Viral infection(hepati

tis), poisons and

toxins(chloroform, carbon

tetrachloride, phosphorus),

cirrhosis

Gallstones, cancer of

pancreas, gall bladder and

bile duct

Type of Jaundice

Pre-Hepatic

Intra-hepatic

Post-Hepatic

Biochemical characteristics

serum unconjugated bilirubin

serum conjugated and unconjugated bilirubin, SGPT and SGOT

Serum conjugated bilirubin and ALP

Clinical manifestations

Dark brown color stools

Nausea and anorexia

Nausea; GI pain and clay colored feces

Stercobilinogen content

Increased Absent Absent

Urobilinogen content

Increased Increased Increased

Etiology/Causes

Common Drugs Associated With Hyperbilirubinemia

HEPATOCELLULAR CAUSES

• Acetominophen• Alcohol• Amiodarone• Azulfidine• Carbenicillin• Clindamycin• Colchicine• Cyclophosphamide• Diltiazem• Ketoconazole• Methyldopa

• Niacin• Nifedipine• NSAIDs• Propylthiouracil• Pyridium• Pyrazinamide• Quinidine • Rifampicin• Salicylates• Verapamil

Common Drugs Associated With Hyperbilirubinemia

CHOLESTATIC CAUSES Amitriptyline

Androgenic steroids (B) Atenolol Augmentin Azathioprine Bactrim (D) Benzodiazeprines Captopril Carbamazole Chlordiazepoxide (D)) Clofibrate Coumadin Cyclosporine Danazol (B) Dapsone Disopyramide Erythromycin Estrogens (B) Ethambutol Floxuridine

5-Flucytosine Fluoroquinolones Griseofulvin Haloperidol (D) Labetolol Nicotinic acid NSAIDs Penicillins Phenobarbital Phenothiazines (D) Phenytoin Tamoxifen Tegretol Thiabendazole (D) Thiazides Thiouracil Tolbutamide (D) Tricyclics (D) Verapamil Zidovudine

1. Increased bilirubin production

2. Reduced bilirubin uptake by hepatic cells

3. Disrupted intracellular conjugation

4. Disrupted secretion of bilirubin into bile canaliculi

5. Intra/extra-hepatic bile duct obstruction

Lead to increases in free (unconj.) bilirubin

Result in rise in conj. bilirubin levels

Etiopathogenesis

1. INCREASED BILIRUBIN PRODUCTION(unconj. Hyperbilirubinemia) Hemolysis

Increased destruction of RBCs eg sickle cell anemia, thalassemia

Drastic increase in the amount of bilirubin produced Unconj. bilirubin levels rise due to liver’s inability to

catch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of

bilirubin salts in the gall bladder and biliary network - result in formation of gallstones and conditions such as cholecystitis and biliary obstruction

Other Degradation of Hb originating from areas of tissue

infarctions and hematomas Ineffective erythropoiesis

2. DECREASED HEPATIC UPTAKE(unconj. Hyperbilirubinemia)

Several drugs have been reported to inhibit bilirubin uptake by the liver

e.g. novobiocin, flavopiridol

Bile

MRP2

B + GST

CB

Plasma Hepatic cell

Alb B

Alb :GSTB

sER

B + UDPGA UGT1A1

Neonatal jaundice occurs in 50% of newborns fetal bilirubin is eliminated by mother’s liver causes:

hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubin rate of bilirubin production is increased due to shorter lifespan of RBCs

Acquired disorders

hepatitis, cirrhosis impaired liver function

3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)

Crigler-Najjar Syndrome, Type I (CN-I)

recessive allele; mutation-induced loss of conjugating ability in the critical enzyme glucuronosyltransferase CN-II greatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugs

Gilbert’s Syndrome glucuronosyl transferase activity

reduced to 10-30% of normal; also accompanied by defective bilirubin uptake mechanism

4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI

(conj. Hyperbilirubinemia)

Dubin–Johnson Syndrome

mild conj. hyperbilirubinemia, but can increase with

concurrent illness, pregnancy, and use of oral contraceptives;

otherwise asymptomatic

Inability of hepatocytes to secrete CB after it has formed

Due to mutation in the MRP2 gene (autosomal recessive trait)

Rotor Syndrome

Autosomal recessive condition characterized by increased

total bilirubin levels due to a rise in CB

Caused by a defect in transport of bilirubin into bile

5) Intra/extra-hepatic bile duct obstruction

Intra-hepaticObstruction of bile canaliculi, bile ductules or hepatic

ducts

Extra-hepaticObstruction of cystic duct or common bile duct

Cholecystitis

Obstruction causes backup and reabsorption of CB which

results in increased blood levels of CB

Signs and

Symptoms Skin and sclerae - yellow

Stool - light colour, clay

coloured

Dark urine

Pain in abdomen

Itching

Trouble with sleeping

Fatigue

Swelling

Ascites

Mental confusion

Coma

Bleeding

Diagnosis

Medical history and examination

Urine test

Liver function and blood tests

Imaging tests

Liver biopsy

Medical history and physical examination

Patient interview for-  abdominal pain, itchy skin or weight loss-  malaria or hepatitis A-  change of colour in your urine and stools- history of prolonged alcohol misuse- Flu like symptoms- Medications- Occupation

Physical examination :- Yellowish discoloration of eye and skin- Swelling of legs, ankle and feet- Hepatomegaly

Urine test :

 - to measure levels of a substance called urobilinogen

- more than normal urobilinogen levels : Pre and Intra

hepatic

jaundice

- Less than normal urobilinogen level : Post hepatic

jaundice

Liver function and blood tests :Damage to liver releases liver enzymes like SGPT,

SGOT and ALP and proteins, this indicates

- Hepatitis

- Alcoholic liver disease

- cirrhosis

Imaging tests

- CT Scan

- MRI Scan

- Ultrasound Scan

- Endoscopic retrograde

cholangiopancreatography (ERCP)

Used  to check for abnormalities inside the liver or

bile duct systems.

Liver biopsy

Used to diagnosis Cirrhosis and liver cancer.

Jaundice treatment

The treatment given to someone with jaundice will depend on what type they have, how serious it is and what caused it.

It may include tackling an underlying condition such as malaria and bothersome symptoms, such as itching.

For genetic conditions that don't get better, like sickle cell anaemia, a blood transfusion may be given to replenish red blood cells in the body.

If the bile duct system is blocked, an operation may be needed to unblock it. During these procedures measures may be taken to help prevent further problems, such as removal of the gallbladder.

If the liver is found to be seriously damaged, a transplant may be an option

Treatment & Therapeutic

Considerations

PHOTOTHERAPY

Through absorption of the wavelengths at the blue end of

the spectrum (blue, green and white light), bilirubin is

converted into water-soluble photoisomers. This

transformation enhances the molecule’s excretion into

bile without conjugation.

PHENOBARBITAL

This drug is not approved by FDA for use in neither

adult nor pediatric hyperbilirubinemia patients, due to

possibility of significant systemic side-effects.

Exact pathway is not known, but it is believed to act as

an inducing agent on UDP-glucuronosyl transferase,

thereby improving conjugation of bilirubin and its

excretion.

ALBUMIN

A 25% infusion can be used in treating

hyperbilirubinemia (esp. due to hemolytic disease).

It is used in conjunction with exchange transfusion to

bind bilirubin, enhancing its removal.

CLOFIBRATE (ATROMID-S)

This drug has been shown to reduce bilirubin levels

via an unknown mechanism.

Clofibrate is also associated with increased risk of

developing cholelithiasis, cholecystitis, as well as

functional liver abnormalities, which can worsen

hyperbilirubinemia.

PERCUTANEOUS TRANSHEPATIC

CHOLANGIOGRAPHY

Allows extraction of stones and thus removal of the

source of obstruction when present.

Prevention of Jaundice :

• Limit alcohol intake to not more than two drinks

a day for men or one drink a day for women.

• Avoid exposure to industrial chemicals.

• Do not use illegal drugs.

• Do not share needles or nasal snorting

equipment.

• Vaccination : Hepatitis A and Hepatitis B

• Maintain healthy body weight.