Lecture 2: Liver Function tests/Ped Jaundice

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

10 hrs Liver, heart, kidney, muscle, brain

48 hrs Liver, heart, kidney

4hrs Liver, heart, kidney, muscle, RBC, tumor

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

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

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.

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.

pathologic

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,

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)

Impaired uptake, conjugation, or secretion of bilirubin Reflects a generalized liver (hepatocyte) dysfunction

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

“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.

Deposits in skin and mucous membranes - JAUNDICE Unconjugated bilirubin deposits in the brain - ACUTE BILIRUBIN ENCEPHALOPATHY Permanent neuronal damage - 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

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)

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

Unconjugated

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

Rotors syndrome Dublin-Johnson Syndrome

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

Genetic disorder that occurs most often in males problem associated with glucose-6-phosphate dehydrogenase deficiency is haemolytic anaemia

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