Hepatobiliary disease

Prepared by: Siti Norhaiza Binti Hadzir

The anatomy of Biliary tract

Bilirubin metabolism• Major metabolite of heme• Heme is found in hemoglobin, myoglobin and

cytocrome.• Most of daily production (0.2 to 0.3g/dL) is

derived from breakdown of senescent erythrocytes

• Rate of systemic bilirubin production is equal to the rates of hepatic uptakes, conjugation, and biliary excretion.

Production of bilirubin

Hepatic transport and conjugation of bilirubin

Hepatic uptake of bilirubin and production of bile

Bilirubin Excretion in the human body

Pathophysiology of jaundice• Disturbance in bilirubin production or

clearance.• It is characterized by yellow color of white of

the eyes (sclera) and skin• Serum bilirubin levels rise above 2.0 to 2.5

mg/dL; level as high as 30-40mg/dL can occur with severe disease

• ↑ also called as hyperbilirubinemia.

Mechanism of jaundice• Excessive production of bilirubin

• Reduced hepatic uptake• Impaired conjugation• Decreased hepato-cellular excretion• Impaired bile flow (both intrahepatic and

extrahepatic)

Aetiology of jaundice

Jaundice

Pre-hepatic Post-hepatic

Hepatic

Pre-hepatic jaundice• Excessive production of bilirubin due to

excessive destruction of red blood cells.• It is associated with increased hemolysis of

erythrocytes (e.g incompatible blood transfusion, malaria, sickle cell anemia).

• This results in overproduction of bilirubin beyond the capacity of the liver to conjugate and excrete bilirubin.

Hepatic jaundice• Defective hepatic uptake• Abnormal conjugation• Hepatocellular damage

Defective hepatic uptake• Unconjugated bilirubin in the plasma is carried into

the liver by intracellular transport proteins.• Absences of these proteins result in failure of

bilirubin uptake, leading to unconjugated hyperbilirubinemia (e.g Gilbert Syndrome).

• Defective of blood supply to the liver also can cause abnormality of bilirubin metabolism

• These problems happen in congestive heart failure, pathway shunt due to surgery or congenital and adverse effect from drug intake.

• Abnormal conjugation

- Partial deficiency of glucoronyl transferase

- drugs may interfere with this enzyme system e.g Novobiocin

• Hepatocellular damage

- Acute or chronic hepatocellular injury

Post hepatic jaundicea) Obstruction or impaired excretion of bilirubin

Failure of transfer of bilirubin glucuronide from the liver cell into the canaliculus (e.g Dubin-Johnson syndrome and Rotor’s syndrome)

b) Obstruction at the intra-hepatic level

(cholestasis)

Obtruction to the flow of bile in the intralobular biliary canaliculli

Post hepatic jaundice: cont; Intra-hepatic cholestasis occurs in: - in viral hepatitis - alcoholic liver disease - as a toxic reaction to drugs, including andrigens

(methyltestosterone), anabolic steroids, oral contraceptives, and phenothiazines

- in benign familial cholestatic jaundice, a rare familial disease in which recurrent attacks of cholestatic jaundice represent the only abnormality

Extra-hepatic obstruction Obtruction involve main hepatic ducts, the common hepatic duct, or common bile duct. Complete obstructive jaundice prevents entry of bilirubin into the intestine, producing pale clay-colored or chalky stools Absence of fecal and urinary urobilinogen dark brown (tea colored) urine containing bilirubin.

Laboratory investigation• Usually, the following examinations are taken:

- FBC (hemolysis)

-serum aminotransferase (AST,ALT)

- Serology for hepatitis including HCAb,HBsAg, HBcAb

- ALP: if elevated or if an obstruction is suspected, images of the bile ducts should be obtained.

- GGT

- Fractionated bilirubin

Laboratory differential diagnosis of jaundice

Hemolytic Cholestatic Hepatocellular

Features Bilirubin usually <75µmol/L

No bilirubin in urine

Reticulocytosis

Hemoglobin ↓

Haptoglobin ↓

LDH may ↑

Bilirubin ↑ ↑ ↑

Bilirubin in urine

ALP more than 3x normal range

AST, ALT,LDH

usually modestly ↑

AST, ALT ↑ ↑

Bilirubin ↑later

Bilirubin in urine

ALP ↑ later

Neonatal jaundice• Jaundice is the most common condition that requires

medical attention in newborns. • In most infants, unconjugated hyperbilirubinemia

reflects a normal transitional phenomenon. • However, in some infants, serum bilirubin levels may

excessively rise, cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus).

• For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.

Pathophysiology of neonatal jaundice• Neonatal jaundice results the following

phenomena:

Increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.

Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid.

Pathophysiology of neonatal jaundice:cont;

Certain factors present in the breast milk of some mothers may contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice). Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin production through increased hemolysis. Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice

Laboratory investigation• A total serum bilirubin level is the only testing

required in an infant with moderately jaundice.• Blood type and Rh determination in mother and

infant • Direct Coombs testing in the infant • Hemoglobin and hematocrit values.• Peripheral blood film for erythrocyte morphology • Reticulocyte count • Tests for viral and/or parasitic infection: These may

be indicated in infants with hepatosplenomegaly or other evidence of hepatocellular disease.

Example

• The liver function tests shown below were those of a 77 year old man with an advanced carcinoma of the colon. The physical examination revealed an enlarged, hard, non-tender liver but there was no evidence of jaundice.

• Plasma

Tprot 64 g/L (60-80)

Alb 35 g/L (30-50)

ALP 725 U/L (30-120)

ALT 78 U/L (<35)

Bili 72 µmol (<20)

-characteristic of cholestatic nature.

-space occupying lesion due to secondary carcinoma

characteristic of cholestatic nature.

-space occupying lesion due to secondary carcinoma

• Very high plasma ALP- obstruction of intrahepatic bile ducts

• Modest increase in the plasma ALT-lesion slowly expanding and destroying hepatocytes

Thank you