Hyperbilirubinemia and Cholestasis

Question 1

Bile + Main Components

Answer 1

• Bile - actual liquid produced and secreted by liver; composed of water, bile salts, bilirubin, electrolytes and lipophilic cholesterol and lipoproteins
• Bilirubin- heme breakdown product excreted via the bile
• Bile Salts - bile acid + cation (Na); emulsify fats for absorption (+ fat soluble vit and drugs) and help eliminate lipophilic toxins

Question 2

Hyperbilirubinemia v. Cholestasis

Answer 2

• Cholestasis - disruption in biliary metabolism; back up of bilirubin –> toxic levels and deposition in numerous tissues
• *Specific Labs - Inc ALP, GGT and 5-NT if blockage
• Hyperbilirubinemia - high bilirubin in serum regardless of presence of cholestasis (true defect in metabolism)

Question 3

Bile Acid Circulation

Answer 3

blood –> sinusoids –> NTCP on basolateral membrane (paired w/ Na-K pump) –> ER for conjugation w/ glycine or taurine in hepatocyte –> pumped out by BSEP (against gradient) —> bile canaliculus –> bile

Question 4

Bilirubin Circulation

Answer 4

blood –> sinusoids –> OATP on basolateral membrane (own pump) –> ER for UDP-glucouronidation (via UDPTG) –> pumped out MRP2 (against gradient) –> bile canaliculus –> bile –> SI

• Bacteria breaks bilirubin down –> urobilinogen
  
  • 1- absorbed in colon –> circulation –> kidney where it is oxidized to urobilin (turns urine yellow)
  • 2- OR stays in colon and oxidized there –> stercobilin (turns stool brown)

Question 5

Bile Flow (2 mechanisms)

Answer 5

1- Bile Acid - Dep Flow: bile in the canaliculi is highly osmotic and thus drags water into lumen as it moves along
- Flow enhanced by secretin

2- Bile Acid - Indep Flow: in ducts, removal of water along w/ NaCl + addition of bicarb to concentrate the bile

**Meal –> CCK –> gallbladder contracts AND sphincter of Oddi relaces –> flow down pressure grad –> duodenum

Question 6

Normal Bilirubin Lab Values

Answer 6

• Total - .3-1.5
• Conjugated - .0-.3
• Unconjugated .1-1.0 (not water soluble so not excreted)

Question 7

Classification of Causes of Hyperbilirubinemia

Answer 7

• Unconjugated
  
  • Hemolysis - pre-hepatic cause; inc RBC death; due to glucose-6-phos dehydrogenase def, sickle cell, drugs (sulfa), etc
  • Neonatal
  • UDPTG Def (genetic disorders)
  • Others - fasting (dec glucose needed for glucouronidation), drugs, hypothyroidism
• Conjugated (if > 30% total bilirubin is conjugated)
  
  • Congenital/ Intrahepatic (conjugated but cannot exit hepatocyte to backs up into circulation) - 3 disorders
  • Acquired/ Intrahepatic - drug interactions, chronic liver disease (late stages of PBC and primary sclerosing cholangitis), alcoholic liver disease, infections (hepatitis), drugs

Question 8

Neonatal Jaundice

Answer 8

• delay in UDPGT function (treat w/ phototherapy or phenobarbital to induce enzyme)
• OR breastfed jaundice b/c maternal milk contains UDPGT inhibitor (cessation)

Question 9

2 UDGPT Deficiency Disorders

Answer 9

• Gilbert’s syndrome - benign dec UDPGT activity; auto rec; usually asymptomatic or jaundice under physio stress
• Crigler Najjar - severe total lack of UDPGT activity; leads to kernicterus and death w/in 18 mo if not aggressively treated; use phototherapy, plasmaphoresis or liver transplant NOT phenobaribtal

Question 10

3 Congenital Conjugated Hyperbilirubin Disorders

Answer 10

• Dubin-Johnson syndrome - benign; auto recessive; impaired storage or excretion thru MRP2; causes black liver from pigmentation but liver function preserved may use phenobarbital
• Rotor’s Syndrome - benign; auto recessive; impaired intracellular storage of organic anions but normal bile salt excretion and normal liver function; no tx needed
• Byler’s Syndrome - defect in secretion of conjugated bile acids across canalicular membrane –> severe watery diarrhea and cholestasis

Question 11

What drugs can cause inc conjugated bilirubin?

Answer 11

oral contraceptives, aspirin, acetaminophen, anti-dep, NSAIDs, niacin, TPN

Question 12

Cholestasis Work Up

Answer 12

• If worried about obstruction, do ab ultrasound
• If see dilated ducts on ultrasound w/ high suspicion then do ERCP (risk but good b/c can also treat w/ scope by removing stones, stenting, etc)
• If not dilated then do specific biochemical tests to eval for other liver diseases

Question 13

Classification of Causes of Cholestasis

Answer 13

• Intrahepatic - impaired uptake, processing or excretion in hepatocyte
  
  • Viral or alcoholic hepatitis
  • Hepatotoxinc agents
  • Drugs - NSAIDs, chlorpromazine, phenobarbital, steroids, etc
  • Prolonged TPN
  • Byler’s Syndrome
• Extrahepatic - impaired delivery from canaliculi to duodenum
  
  • PBC
  • Primary sclerosing cholangitis
  • Common bile duct stones (choledocolithiasis)
  • Pancreatic carcinoma at head of pancreas
  • Pancreatitis (if head inflammed)
  • Biliary stricture/ ampulla of Vater stenosis
  • Ampulla of Vater neoplasm
  • Mirizzi’s Syndrome (stone in cystic duct neck that impinges on common bile duct)
  • Parasite obstructing common bile duct
  • Post-operative trauma

Question 14

Clinical Manifestations of Cholestasis

Answer 14

EXCESS bilirubin in…

• Serum - hyperbilirubinemia and pruritus (itching)
• Sclera - scleral icterus (b/c elastin there)
• Skin - jaundice
• Brain - kernicterus (encephalopathy)
• Dark urine (excess in urine) or light stool (no bile in stool if obstruction)

ALSO …

• Mal-digestion and malabsorption of fats (def in fat-soluble vit and steatorrhea)
• Impaired cholesterol excretion –> xanthomas