Liver Flashcards
Jaundice
results from the retention of bile
Serum bilirubin levels in jaundice
> 2mg\dl
Causes of jaundice
Predominantly Unconjugated Hyper-bilirubinaemia
Excess Production of Bilirubin
Reduced Hepatic Uptake
Impaired Bilirubin Conjugation
Pathogenesis of Jaundice
Disruption of the equilibrium between Bilirubin production and clearance; Bilirubin is the end product of heme degradation.
Clinical Manifestation of Jaundice
Patients with a yellow discolouration of skin and sclerae (icterus)
Neonatal Jaundice
Due to immaturity of the liver in conjugating and excreting Bilirubin → Development of transient and mild unconjugated hyper-bilirubinaemia (until ~2 weeks of age)
Unconjugated Bilirubin
Insoluble in water at physiologic pH
Exists in tight complexes with serum albumin
Cannot be excreted in the urine
Small amount of unconjugated Bilirubin, present as an albumin-free anion in plasma
Increase of this unbound fraction (e.g., in haemolytic disease of the newborn [erythroblastosis fetalis]) can lead to accumulation of unconjugated Bilirubin in the brain → Kernicterus
Conjugated Bilirubin
Water-soluble
Non-toxic
Loosely bound to albumin
Can be excreted in urine
Bilirubin delta fraction: With prolonged conjugated hyper-bilirubinaemia, a portion of circulated pigment becomes covalently bound to albumin
Equilibrium Disturbance: Jaundice
The equilibrium between Bilirubin production and clearance can be disturbed by one or more of the following mechanisms:
Excessive extra-hepatic production of Bilirubin
Reduced hepatocyte uptake
Impaired conjugation
Decreased hepatocellular excretion
Impaired bile flow
Unconjugated Hyper-bilirubinaemia
Caused by mechanisms 1, 2, or 3 (Excessive extra-hepatic production of Bilirubin, Reduced hepatocyte uptake, Impaired conjugation)
Conjugated Hyper-bilirubinaemia
Caused by mechanisms 4 or 5 (Decreased hepatocellular excretion, Impaired bile flow)
Hereditary Hyperbilirubinemias types
Crigler-Najjar Syndrome
Gilbert Syndrome
Dubin-Johnson Syndrome
Rotor Syndrome
Crigler-Najjar Syndrome
Mutations in the UGT1A1 gene → Deficient bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme
Crigler-Najjar Syndrome: Types
Type 1 (CN1): Very severe; no enzyme function; affected individuals can die in childhood due to Kernicterus.
Type 2 (CN2): Less severe; <20% of normal enzyme’s function; people with CN2 are less likely to develop Kernicterus, and most affected individuals survive into adulthood.
Crigler-Najjar Syndrome: Frequency
Less than 1 in 1 million newborns worldwide.
Crigler-Najjar Syndrome: Clinical Manifestations
Jaundice, at birth or in infancy
Severe unconjugated hyper-bilirubinaemia → Kernicterus
Kernicterus: Clinical Picture
Extremely tired (lethargic)
Weak muscle tone (hypotonia)
Episodes of increased muscle tone (hypertonia) and arching of the backs
Involuntary writhing movements of the body (choreo-athetosis)
Hearing problems, or intellectual disability
Gilbert Syndrome
Benign, inherited (autosomal recessive) condition
Relatively common; 7% of the population
Gilbert Syndrome: Cause
Most cases: Homozygous insertion of two extra bases in the 5’ promoter region of the UGT1A1 gene → Reduced transcription
In Gilbert syndrome, hepatic bilirubin-glucuronidation activity is about 30% of normal, a less severe reduction than in Crigler-Najjar syndromes.
Gilbert Syndrome: Clinical Manifestations
Mild fluctuating hyper-bilirubinaemia, in the absence of haemolysis or liver disease; it may remain undetected for years and is not associated with functional derangements
Gilbert Syndrome patients, more susceptible to adverse effects of drugs that are metabolized by UGT1A1
Dubin-Johnson Syndrome
Autosomal recessive disorder, characterized by chronic conjugated hyper-bilirubinemia
Cause: Absence of the canalicular protein, multidrug resistance protein 2 ([MRP2]; responsible for the transport of bilirubin glucuronides & related organic anions into bile)
Dubin-Johnson Syndrome: Pathogenesis
Defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane
Dubin-Johnson Syndrome: Clinical Manifestations
Chronic or recurrent Jaundice of fluctuating intensity
Macroscopic findings: Darkly pigmented liver
Microscopic findings: Coarse pigmented granules within the cytoplasm of hepatocytes
Rotor Syndrome
Rare form of asymptomatic conjugated hyperbilirubinemia
