Biliary Secretions

Question 1

Liver Cirrhosis

Answer 1

• Chronic liver disease in which normal liver cells are damaged and replaced with car tissue
• Excessive alcohol intake is the most common cause of cirrhosis
• Alcohol abuse leads to accumulation of fat within hepatocytes
• Fatty liver leads to steatohepatitis

Steatohepatitis: fatty liver accompanies by inflammation which leads to scarring and liver cirrhosis

Question 2

Portal Hypertension

Answer 2

• One of the most common causes of portal hypertension worldwide is cirrhosis
• With Cirrhosis, you will see engorgement of capillaries, veins and arteries and the creation of an alternate pathway for the release of pressure associated with tissue scarring
• Develops when there is resistance to portal blood flow – which most often occurs in the liver
• Leads to the development of:
  o Esophageal varices
  o Caput Medusae
  o Hemorrhoids

Question 3

Esophageal Varices

Answer 3

o Engorgement of the veins that go to the esophagus
o Swollen connection between systemic and portal systems at the inferior end of the esophagus
o Between the left gastric vena and the esophageal gastric veins/ azygous veins

Question 4

Caput Medusae

Answer 4

o Swollen connections between the systemic and portal systems around the umbilicus
o Cause by Cirrhosis and advanced liver damaged
o Superficial vein along the abdominal wall – portal HT engorges
o Goes through the umbilicus

Question 5

How does liver dysfunction cause Encephalopathy?

Answer 5

• Decreased hepatic urea metabolism in the context of liver cirrhosis or portosystemic shunting leads to accumulation of ammonia in the systemic circulation
• Ammonia readily crosses the BBB and alters brain function
• The liver manages the conversion of ammonia to urea, without this conversion you will have high levels of ammonia in circulation.
• These can reach the brain by crossing the BBB and cause:
  o Changes in osmotic osmotic balances in the brain
  o Increased brain water
  o Direct neuronal toxicity
  o Increased intracranial pressure
  o Altered neurotransmission

Question 6

Jaundice (Icterus)

[Heme]

Answer 6

• Sign of hyperbilirubinemia
• Yellow discoloration of the sclera, skin and mucous membrane
• Measurement of the total serum (bilirubin) allows the quantification of jaundice
• Bilirubin test results are expressed as direct (conjugated) or indirect (unconjugated) or total bilirubin

Question 7

Hemolytic Anemia
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?
Symptoms?

Answer 7

Unconjugated Jaundice

• High RBC breakdown
• Increased levels of Bilirubin and unconjugated jaundice
• Increased bilirubin will overwhelm the liver’s capacity to produce conjugated bilirubin, results in increased UNCONJUGATED BILIRUBIN

Symptoms:
Jaundice:

1. Cholestasis –> Gallstones, rise in ALP
   - Pale stools, dark urine
2. Hepatocellular –> rise in AST/ ALT
   problem with the hepatocytes releasing conjugated bile

Question 8

Physiological Neonatal Jaundice
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 8

Unconjugated Jaundice

• Increased unconjugated bilirubin in blood during the 1st week post natal age
• 2 main causes:
  1. Bilirubin production is elevated because of increased breakdown of fetal erythrocytes- shortened lifespan of fetal erythrocytes
  2. Low activity of UDP glucuronyl transferase
• Sometimes, infants with jaundice may be tired and poorly fed

Question 9

Gilbert Syndrome (asymptomatic)
ADOLESCENCE, MILD
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 9

a. Increased levels of unconjugated bilirubin in the blood
b. Relatively mild, individuals can live asymptomatic lives ~30%
c. Usually recognized during the adolescence
d. If people with this condition have episodes of hyperbilirubinemia, these episodes are generally mild and typically occur when the body is under physical stress
e. Mutation in gene that encodes for uridine diphosphate glucuronosyltransferase (UDP glucuronyltransferase)

i. Additional factors that interferes with the glucuronidation process may be necessary for the development of the condition - problems with OATP, NCTP getting the unconjugated Br into the hepatocyte - hepatocyte membrane
- Movement of bilirubin into the liver, where it would be glucuronidated, may be impaired

Treatments:
-Phenobarbitol

Question 10

Crigler-Najjar Syndrome
BIRTH
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 10

a. Increased levels of unconjugated bilirubin in the blood
b. Nonhemolytic jaundice
c. Mutations in the gene that codes for UDP glucuronyltransferase unable to conjugate causes increased levels of unconjugated bilirubin
d. Divided into two subtypes:
i. Type 1 (CN1): very severe
ii. Type 2 (CN2: less severe

Question 11

Crigler-Najjar Syndrome Type 1 (CN1)
Homozygous mutation in UDP- GT
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 11

Unconjugated Bilirubin

a. Starts early in life – genetic mutation
b. SEVERE
c. NO FUNCTION OF UDP glucuronyltransferase
d. Kernicterus: form of brain damage caused by the accumulation of unconjugated bilirubin in the brain tissue – chronic/ permanent effects of unconjugated Bilirubin unconjugated Bilirubin CAN cross the BBB and has toxic proeprties if it reaches the brain it can alter the viability of the neurons within the cells and cause neurodegeneration
e. Before the availability of phototherapy, patients died of kernicterus or survived until early adulthood with clear neurological impairment

Question 12

Crigler-Najjar Syndrome Type 2 (CN2)
Heterozygous Mutation in UDP-GT
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 12

Unconjugated Bilirubin

a. LESS SEVERE
b. Starts later in life
c. Less than 20% of the UDP glucuronyltransferase is functional
d. Less likely to develop kernicterus
e. Most affected individuals survive into childhood

Question 13

Dubin Johnson
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 13

Conjugated Bilirubin

a. Increased conjugated bilirubin in the serum without elevation of liver enzymes
i. Defect in the ability of the hepatocytes to secrete conjugated bilirubin into the bile
ii. Mutations in the multidrug resistance protein 2 (MRP2)- transports bilirubin out of the liver cells into bile *
- -> CANALICULAR MEMBRANE
b. Mild jaundice throughout life
i. May not appear until puberty or adulthood
ii. Usually the only symptom
iii. May be worse by: alcohol, birth control pills, infection, pregnancy
c. Liver has black pigmentation*
i. Results of an intracellular melanin-like substance but is otherwise histologically normal

Question 14

Rotor System
[Heme]

Conjugated or Unconjugated Bilirubin?
What causes it?

Answer 14

Rotor System: BOTH – Unconjugated Bilirubin and Conjugated Bilirubin

a. Majority is conjugated
b. Similar to dubin-johnson
c. Gene mutations that lead to abnormally short, nonfunctional OATPB1 and OATP1B3 proteins or absence of these proteins
i. These proteins normally transport bilirubin and other compounds from the blood into the liver so that they can be cleared form the body
d. Liver cells are not pigmented

• Jaundice
• No pigmented Lier
• Liver biopsy

Question 15

Acute Intermittent Porphyria

[Heme]

Answer 15

Defective Enzyme: PBG Deaminase (Hepatic)
Excessive Ala and PBG
Symptoms: periodic attacks of abdominal pain/ neurologic dysfunction

Question 16

Porphyria Cutanea Tarda

[Heme]

Answer 16

Defective enzyme: uroporphyrinogen decarboxylase
leads to increased uro-porphyrinogen III –> uro-porphyrinogen I

• photosensitivity results in vesicles and bull on skin and exposed area
• Red wine colored urine

Question 17

Wilson’s Disease
[Copper]
Teens

Answer 17

Autosomal recessive mutation in CTR1 –> copper transport protein located in hepatocytes

CTR1–> ATP7B (Bile canaliculi membrane)

Copper is unable to be excreted into the bile by the liver
Failure of copper to enter circulation bound to ceruloplasmin (transport protein for copper)

Increase in free copper
Free copper will generate free radicals that will damage tissues

Symptoms - seen in TEENS:
-Kayser Fleischer Rings - eyes
-Abdominal pain
-Uncontrolled limb movements and stiffness
*PARKINSON’S LIKE
Hemiballismus: flailing, ballistic undesired movements of th limbs
Dementia/ forgetfulness

Question 18

Hemochromatosis
[Iron]
40-60 year olds

Answer 18

Autosomal recessive mutation
HFE- Hepcidin –> ferroportin

Normal total body iron is 3-5g
Hemochromatosis: 15g

Symptoms are related to conditions that arise from iron overload such as diabetes, darkening of the skin, abnormal heart rhythm, or arthritis.

• Darkly pigmented skin
• Cardiac issues –> arrhythmias
• Hepatitis (build up of iron in the liver)
• Arthritis
• Diabetes

Serum testing:
Total Iron Binding Capacity
Rises from 30% normal to 60% ABNORMAL
and decreased availability of transferrin

Question 19

Galactosemia
[Carbohydrate metabolism - galactose]
Babies

Answer 19

AR mutation
galactose digesting enzymes
GALT - Type 1 Galactosemia
converts galactose-1-P to glucose-1-P

Causes a build up of galactose

Symptoms: *BABIES

Acute:
Galactose is found in milk (lactose = glucose and galactose) - infants are unable to utilize - galactose is not converted to glucose for energy, it is accumulating in tissues
- Infant suffers from malnutrition, failure to thrive
- Jaundice
- Hepatomegaly –> galactose-1-phosphate build up
- Vomiting
- Diarrhea

Chronic:

• Baby will have problems drinking milk
• Build up in the neural tissue can cause permanent neural defects
• Cataracts * in a few weeks

Question 20

Hereditary Fructose Intolerance
[Carbohydrates - Fructose]
Early Manifestations

Answer 20

LIVER

AR mutation in
Aldolase B - [ALDOB] - breaks down fructose-1-phosphate into glyceraldehyde and DHAP
accumulation of fructose-1-phosphate

• Manifests early
• nausea/vomiting
• Pallor
• sweating
• lethargic

*WHEN EXPOSED TO FRUITS/ VEGGIES

Question 21

Von Gierke Disease
[Glycogen storage disease]
3-4 month

Answer 21

AR in Glucose-6-phosphatase
this is the enzyme that removes phosphate from glucose to allow it into circulation. Without this enzyme functioning, there is an increase in glycogen –> too much glucose-6-phosphate in the liver

Symptoms:

• Hepatomegaly
• HYPO-glycemia
• Lactic acidosis

Question 22

PEPCK Disease

[Pyruvate]

Answer 22

GNG - occurs in the liver* and kidneys taking glycogen and extrahepatic sources –> glucose

AR mutation in PEPCK enzyme in GNG

Extrahepatic sources include:

• Alanine (muscle)
• Lactate (muscle/ RBC)
• Glycerol (adipose tissue) *** can be used to treat the hypoglycemia symptoms

These patients have an increase/ buildup in pyruvate which is the first step necessary to make glucose

Symptoms

• Build up of alanine and lactate in the blood
• Hypoglycemia
• increase liver enzymes
• hepatomegaly –> caused by increase pyruvate
• Failure to thrive
• VERY RARE

Question 23

Biliary Atresia

Answer 23

2-6 weeks of age***

Biliary Atresia - extra hepatic ductopenia and progressive obliterative cholangiopathy
Childhood disease of the liver
Bile ducts are abnormally narrow/ blocked - bile will back up into the liver and spill into the blood

Symptoms: appears 2-6 weeks AFTER BIRTH
Dark yellow to brown urine - due to excessive Br in the bloodstream that will pass to the kidneys
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