Lecture 2: Liver Function tests/Ped Jaundice

Question 1

Markers of hepatic injury

Answer 1

Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Lactate dehydrogenase (LDH)

Question 2

What is AST half life and where is it located

Answer 2

10 hrs

Liver, heart, kidney, muscle, brain

Question 3

What is ALT half life and where is it located

Answer 3

48 hrs

Liver, heart, kidney

Question 4

What is LDH half life and where is it located

Answer 4

4hrs

Liver, heart, kidney, muscle, RBC, tumor

Question 5

Markers for Cholestasis/obstruction

Answer 5

Alkaline phosphatase (ALP)
Gamma-glutamyltransferase (GGT) (good for alcoholism)
Bilirubin

Question 6

What is Cholestasis

Answer 6

Cholestasis (lack of bile flow) results from the blockage of bile ducts or from a disease that impairs bile formation in the liver itself.

Question 7

What is the process of unconjugated bilirubin becoming conjugated?

Answer 7

Ligandins responsible for transport from plasma membrane to endoplasmic reticulum.

1. Albumin carries bilirubin to the cell
2. Albumin is removed and ligandins transport bilirubin into the cell to the endoplasmic reticulum
3. UDP-glucuronyl transferase converts the bilirubin + UDP glucuronate to UDP and bilirubin diglucuronide
4. bilirubin diglucuronide excreted from the cell via bile canuliculi.

Question 8

Desrcibe/draw the process of bilirubin metabsolims from pre-hepatic to hepatic to post hepatic

Answer 8

PRE HEPATIC:
RBC haemolysis - Heme - Bilirubin - albumin+bilirubin in circulation

HEPATIC:
Bilirubin+albumin to UDP-glucuronyl transferase converts this to bilirubin diglucuronide

POST HEPATIC:
bilirubin diglucuronide - canuliculi - Bile ducts - ampulla of vater - small bowel - urobilingen excreted.

Question 9

is conjugated hyperbilirubinemia pathologic or physiologic

Answer 9

pathologic

Question 10

Jaundice in terms of pre hepatic, hepatic and post hepatic in terms if the bile is CONJUGATED or UNCONJUGATED and examples of causes

Answer 10

Pre-Hepatic (Acholuric) - Haemolytic
Unconjugated/Indirect Bil, pale urine

Hepatocellular Jaundice - Viral
Liver damage - unconjugated
Swelling, canalicular obstruction - Conjugated

Post Hepatic (Obstructive) – Stone, tumor
Conjugated/Direct Bil, High colored urine,

Question 11

Describe Pre hepatic jaundice

Answer 11

Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis

Excess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease); or breakdown of extravasated blood

High plasma concentrations of unconjugated bilirubin (pre liver issues) (normal concentration ~0.5 mg/dL)

Question 12

Describe Intrahepatic jaundice

Answer 12

Impaired uptake, conjugation, or secretion of bilirubin

Reflects a generalized liver (hepatocyte) dysfunction

Question 13

Describe Posthepatic jaundice

Answer 13

Caused by an obstruction of the biliary tree

Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma

Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)

In a complete obstruction, urobilin is absent from the urine

Question 14

What is kernicterus?

Answer 14

“Kernicterus” refers to the neurologic consequences of unconjugated bilirubin deposited in the brain.
This can cause damage to the basal ganglia and brain-stem.

Serum unconjugated bilirubin level exceeds the binding capacity of albumin and unbound lipid-soluble bilirubin crosses the blood-brain barrier.

Question 15

Development of jaundice to kericterus in terms of bilirubin deposits

Answer 15

Deposits in skin and mucous membranes - JAUNDICE

Unconjugated bilirubin deposits in the brain - ACUTE BILIRUBIN ENCEPHALOPATHY

Permanent neuronal damage - KERNICTERUS

Question 16

Symptoms of acute encephalopathy/kernicterus

Answer 16

Irritability, jitteriness, increased high-pitched crying
Lethargy and poor feeding
Back arching
Apnea
Seizures 

Long-term: Choreoathetoid CP, upward gaze palsy, SN hearing loss, dental dysplasia

Question 17

How is hyperbilirubinemia measured?

Answer 17

Transcutaneous measurement:
Use can reduce need for blood level monitoring

Blood level measurement:
- all babies checked at 24h of life
- Measure Total and Direct Bilirubin levels
Decisions for treatment based on total serum bilirubin (TSB)

Question 18

Define hereditary hyperbilirubinemia

Answer 18

Hereditary hyperbilirubinemia may be caused by increased bilirubin production, mostly as a result of hyperhaemolysis, or decreased bilirubin clearance.

Question 19

Is Crigler-Najjar and Gilberts unconjugated or conjugated?

Answer 19

Unconjugated

Question 20

Causes of unconjugated hyperbilirubinemia

Answer 20

Physiological jaundice
G6PD defeciency
Defective bilirubin uptake by hepatocytes
Crigler–Najjar Syndrome 1 and II
Gilbert Syndrome.

Question 21

Causes of conjugated hyperbilirubinemia

Answer 21

Rotors syndrome

Dublin-Johnson Syndrome

Question 22

Physiologic Jaundice

Answer 22

Progressive rise in total bilirubin between 48 and 120 hours of life (peaks at 72-96 hours)

Due to higher postnatal load of bilirubin and lower amount of liver conjugating enzyme (UGT) activity

Question 23

Glucose-6-phosphate dehydrogenase deficiency

Answer 23

Genetic disorder that occurs most often in males

problem associated with glucose-6-phosphate dehydrogenase deficiency is haemolytic anaemia

Question 24

Defective bilirubin uptake by hepatocytes, leading to unconjugated hyperbilirubinemia due to…

Answer 24

linked to polymorphisms in SLCO1B1
SLCO1B1gene provides instructions for making a protein called organic anion transporting polypeptide 1B1, or OATP1B1
OATP1B1 protein transports bilirubin, which is a yellowish substance that is produced when red blood cells are broken down

Question 25

OATP1B1 purpose..

Answer 25

OATP1B1 allows the process of Ligandin
binding to UCB and therefore the uptake of
UCB into the cell. If there is a mutation in
Oat then the bilirubin remains unconjugated
and unable to be uptaken by the cell.

Question 26

Describe Crigler-Najjar syndrome

Answer 26

Characterized by major unconjugated hyperbilirubinemia (100–750 mmol/L) due to UGT1A1 mutations

Question 27

Describe Type 1 CN

Answer 27

Bilirubin levels are 350 to 750 mmol/L

UGT1A1 mutations result in a complete or near-complete loss of UGT1A1 enzyme activity.

Question 28

Describe Type 2 CN

Answer 28

Bilirubin levels are 100 to 400 mmol/L

UGT1A1 activity is <10% of normal but not completely abolished.

Question 29

Describe Gilberts Syndrome

Answer 29

Characterized by mild, predominantly unconjugated hyperbilirubinemia without hyperhemolysis

Usually occurs in young adults with otherwise normal liver test results

GS is autosomal recessive disorder.

Several mutations in the coding regions of the UGT1A1 gene (rather than the promoter region) have been shown to result in proteins with only mildly reduced enzymatic activity

only shows when stressed or anxious

Question 30

Describe Dubin-Johnson syndrome

Answer 30

Chronic low-grade jaundice associated with a black liver, plasma retention of predominantly conjugated bilirubin and organic anionic compounds

Results from mutations in the protein encoded by ABCC2

transports bilirubin out of liver cells and into bile

Question 31

Describe Rotors Syndrome

Answer 31

Characterized by low-grade (40–100 mmol/L), chronic or fluctuating, predominantly conjugated hyperbilirubinemia.

Suggest that homozygous mutations of the human OATP genes SLCO1B1 and SLCO1B3 on chromosome 2, inducing complete OATP1B1 and OATP1B3 deficiency

Disrupt hepatic reuptake of bilirubin conjugates and lead to accumulation of conjugated bilirubin in blood

Question 32

3 types of pathologic conjugated bilirubin branches and example

Answer 32

1. Non hemolytic (Crigler and Gilberts)
   2.Hemolytic intrinstic (G6PD deficency)
   3.Hemolytic extrinstic (ABO incomp)

Question 33

What is the role of the following:
G6PD
UGT
UGT1A1
OAT1P1/OAT1B1
OAT1B3
ABCC2

Answer 33

G6PD: Prevent premature RBC lysis
UGT: enzyme used for conjugation
UGT1A1: provide instructions for making enzymes called UDP-glucuronosyltransferases.
OAT1P1: transports bilirubin
OAT1B1/OAT1B3: Reuptake of conjugated bilirubin into hepatocyte
ABCC2: Transport conjugated bilrubin out of hepatocyte

Question 34

What blood system is blocked and what blood system is the blood reverted to in cirrhosis?

Answer 34

circulatory system starts diverting blood away from the liver because blood flow follows the path of least resistance and shunts away from the portal system and towards the systemic system of circulation (portosystemic shunt)