Lecture 2: Liver Function tests/Ped Jaundice Flashcards
Markers of hepatic injury
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Lactate dehydrogenase (LDH)
What is AST half life and where is it located
10 hrs
Liver, heart, kidney, muscle, brain
What is ALT half life and where is it located
48 hrs
Liver, heart, kidney
What is LDH half life and where is it located
4hrs
Liver, heart, kidney, muscle, RBC, tumor
Markers for Cholestasis/obstruction
Alkaline phosphatase (ALP)
Gamma-glutamyltransferase (GGT) (good for alcoholism)
Bilirubin
What is Cholestasis
Cholestasis (lack of bile flow) results from the blockage of bile ducts or from a disease that impairs bile formation in the liver itself.
What is the process of unconjugated bilirubin becoming conjugated?
Ligandins responsible for transport from plasma membrane to endoplasmic reticulum.
- Albumin carries bilirubin to the cell
- Albumin is removed and ligandins transport bilirubin into the cell to the endoplasmic reticulum
- UDP-glucuronyl transferase converts the bilirubin + UDP glucuronate to UDP and bilirubin diglucuronide
- bilirubin diglucuronide excreted from the cell via bile canuliculi.
Desrcibe/draw the process of bilirubin metabsolims from pre-hepatic to hepatic to post hepatic
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.
is conjugated hyperbilirubinemia pathologic or physiologic
pathologic
Jaundice in terms of pre hepatic, hepatic and post hepatic in terms if the bile is CONJUGATED or UNCONJUGATED and examples of causes
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,
Describe Pre hepatic jaundice
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)
Describe Intrahepatic jaundice
Impaired uptake, conjugation, or secretion of bilirubin
Reflects a generalized liver (hepatocyte) dysfunction
Describe Posthepatic jaundice
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
What is kernicterus?
“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.
Development of jaundice to kericterus in terms of bilirubin deposits
Deposits in skin and mucous membranes - JAUNDICE
Unconjugated bilirubin deposits in the brain - ACUTE BILIRUBIN ENCEPHALOPATHY Permanent neuronal damage - KERNICTERUS
Symptoms of acute encephalopathy/kernicterus
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
How is hyperbilirubinemia measured?
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)
Define hereditary hyperbilirubinemia
Hereditary hyperbilirubinemia may be caused by increased bilirubin production, mostly as a result of hyperhaemolysis, or decreased bilirubin clearance.
Is Crigler-Najjar and Gilberts unconjugated or conjugated?
Unconjugated
Causes of unconjugated hyperbilirubinemia
Physiological jaundice
G6PD defeciency
Defective bilirubin uptake by hepatocytes
Crigler–Najjar Syndrome 1 and II
Gilbert Syndrome.
Causes of conjugated hyperbilirubinemia
Rotors syndrome
Dublin-Johnson Syndrome
Physiologic Jaundice
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
Glucose-6-phosphate dehydrogenase deficiency
Genetic disorder that occurs most often in males
problem associated with glucose-6-phosphate dehydrogenase deficiency is haemolytic anaemia
Defective bilirubin uptake by hepatocytes, leading to unconjugated hyperbilirubinemia due to…
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
OATP1B1 purpose..
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.
Describe Crigler-Najjar syndrome
Characterized by major unconjugated hyperbilirubinemia (100–750 mmol/L) due to UGT1A1 mutations
Describe Type 1 CN
Bilirubin levels are 350 to 750 mmol/L
UGT1A1 mutations result in a complete or near-complete loss of UGT1A1 enzyme activity.
Describe Type 2 CN
Bilirubin levels are 100 to 400 mmol/L
UGT1A1 activity is <10% of normal but not completely abolished.
Describe Gilberts Syndrome
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
Describe Dubin-Johnson syndrome
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
Describe Rotors Syndrome
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
3 types of pathologic conjugated bilirubin branches and example
- Non hemolytic (Crigler and Gilberts)
2.Hemolytic intrinstic (G6PD deficency)
3.Hemolytic extrinstic (ABO incomp)
What is the role of the following:
G6PD
UGT
UGT1A1
OAT1P1/OAT1B1
OAT1B3
ABCC2
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
What blood system is blocked and what blood system is the blood reverted to in cirrhosis?
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)
