Liver

Question 1

Jaundice

Answer 1

results from the retention of bile

Question 2

Serum bilirubin levels in jaundice

Answer 2

> 2mg\dl

Question 3

Causes of jaundice

Answer 3

Predominantly Unconjugated Hyper-bilirubinaemia
Excess Production of Bilirubin
Reduced Hepatic Uptake
Impaired Bilirubin Conjugation

Question 4

Pathogenesis of Jaundice

Answer 4

Disruption of the equilibrium between Bilirubin production and clearance; Bilirubin is the end product of heme degradation.

Question 5

Clinical Manifestation of Jaundice

Answer 5

Patients with a yellow discolouration of skin and sclerae (icterus)

Question 6

Neonatal Jaundice

Answer 6

Due to immaturity of the liver in conjugating and excreting Bilirubin → Development of transient and mild unconjugated hyper-bilirubinaemia (until ~2 weeks of age)

Question 7

Unconjugated Bilirubin

Answer 7

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

Question 8

Conjugated Bilirubin

Answer 8

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

Question 9

Equilibrium Disturbance: Jaundice

Answer 9

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

Question 10

Unconjugated Hyper-bilirubinaemia

Answer 10

Caused by mechanisms 1, 2, or 3 (Excessive extra-hepatic production of Bilirubin, Reduced hepatocyte uptake, Impaired conjugation)

Question 11

Conjugated Hyper-bilirubinaemia

Answer 11

Caused by mechanisms 4 or 5 (Decreased hepatocellular excretion, Impaired bile flow)

Question 12

Hereditary Hyperbilirubinemias types

Answer 12

Crigler-Najjar Syndrome
Gilbert Syndrome
Dubin-Johnson Syndrome
Rotor Syndrome

Question 13

Crigler-Najjar Syndrome

Answer 13

Mutations in the UGT1A1 gene → Deficient bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme

Question 14

Crigler-Najjar Syndrome: Types

Answer 14

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.

Question 15

Crigler-Najjar Syndrome: Frequency

Answer 15

Less than 1 in 1 million newborns worldwide.

Question 16

Crigler-Najjar Syndrome: Clinical Manifestations

Answer 16

Jaundice, at birth or in infancy
Severe unconjugated hyper-bilirubinaemia → Kernicterus

Question 17

Kernicterus: Clinical Picture

Answer 17

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

Question 18

Gilbert Syndrome

Answer 18

Benign, inherited (autosomal recessive) condition
Relatively common; 7% of the population

Question 19

Gilbert Syndrome: Cause

Answer 19

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.

Question 20

Gilbert Syndrome: Clinical Manifestations

Answer 20

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

Question 21

Dubin-Johnson Syndrome

Answer 21

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)

Question 22

Dubin-Johnson Syndrome: Pathogenesis

Answer 22

Defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane

Question 23

Dubin-Johnson Syndrome: Clinical Manifestations

Answer 23

Chronic or recurrent Jaundice of fluctuating intensity
Macroscopic findings: Darkly pigmented liver
Microscopic findings: Coarse pigmented granules within the cytoplasm of hepatocytes

Question 24

Rotor Syndrome

Answer 24

Rare form of asymptomatic conjugated hyperbilirubinemia

Question 25

Rotor Syndrome cause

Answer 25

unknown

Question 26

Rotor Syndrome: Pathogenesis

Answer 26

Multiple defects in hepatocellular uptake and excretion of Bilirubin pigments

Question 27

Rotor Syndrome: Clinical Manifestations

Answer 27

Jaundice

Question 28

Rotor Syndrome: Macroscopic findings

Answer 28

Normal liver

Question 29

Pathogenesis of alcohol liver diesease

Answer 29

Short-term alcohol consumption → Mild, reversible Hepatic Steatosis

Question 30

Factors that influence the development and severity of alcoholic liver disease

Answer 30

• Gender: Women more susceptible than men
• Ethnic differences
• Genetic factors: Genetic polymorphisms in detoxifying enzymes and some
  cytokine promoters
• Co-morbid conditions: Iron overload and infections (HBV and HCV) →
  Increase in the severity of alcoholic liver disease

Question 31

Pathologic condition of impaired bile formation and bile flow, leading to accumulation of bile pigment in the hepatic parenchyma.

Answer 31

Cholestasis

Question 32

Causes of cholestasis

Answer 32

Extra-hepatic or intra-hepatic obstruction of bile channels
Defects in hepatocyte bile secretion

Question 33

Clinical Manifestations of Cholestasis

Answer 33

Jaundice
Pruritus
Skin Xanthomas (focal accumulations of Cholesterol)

Question 34

Laboratory Findings: Cholestasis

Answer 34

Elevated serum alkaline phosphatase
Elevated serum γGlutamyl Transpeptidase (γGT)
Nutritional deficiencies of the fat-soluble Vitamins A, D, E, or K

Question 35

Pathogenesis/Morphology: Cholestasis

Answer 35

Accumulation of bile pigment within hepatocytes → Fine, foamy appearance (feathery degeneration)
Elongated green-brown plugs of bile in dilated bile canaliculi
Phagocytosis of bile by Kupffer cells
Bile stasis and back-pressure → Proliferation of the duct epithelial cells + Looping and reduplication of ducts and ductules in the portal tracts
Portal tract oedema and periductal infiltrates of neutrophils
Prolonged obstructive cholestasis → Focal dissolution of hepatocytes (by detergents) → Formation of bile lakes, filled with cellular debris and pigment
Unrelieved obstruction → Portal tract fibrosis → Biliary Cirrhosis