1-20 Liver Metabolism and Urea Cycle Flashcards Preview

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Flashcards in 1-20 Liver Metabolism and Urea Cycle Deck (67)
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1

What is bilirubin? How is gotten rid of, in a general sense?

Bilirubin is the orange-yellow pigment derived from senescent red blood cells
- It is a bile pigment

It is a toxic waste product in the body

It is extracted and biotransformed mainly in the liver, and excreted in bile and urine

2

Where does bilirubin come from? How is it disposed of? What organs are involved? What is an important enzyme involved?

RBC when old or damaged are disposed in the spleen

Hb are broken down to heme and globin

Globin are reused as amino acid, and heme are taken up by reticoendothelial cells of the spleen and called unconjugated bilirubin (lipid soluble)

Bilirubin (from RBC breakdown) is transported to liver in blood stream bound to albumin and is taken up by hepatic cells

In liver cells, bilirubin is conjugated by addition of glucuronic acid to produce bilirubin diglucuronide (conjugated or water-soluble bilirubin). This reaction is catalyzed by uridyldiphosphate glucuronyl transferase (UDPGT)

Elevations in serum and urine bilirubin levels are normally associated with jaundice

3

How much bilirubin does an average person produce per day?

4 mg/kg per day, totaling 250-300 mL

4

What is the breakdown of components of bilirubin?

85% - Hb from senescent RBCs destroyed in reticuloendothelial cells of liver, spleen, and bone marrow

15% - RBC precursors destroyed in bone marrow
Catabolism of heme-containing proteins

5

How is bilirubin excreted from the liver, and in what form?

Conjugated bilirubin flows into bile ducts and is secreted with bile into intestines

Converted to urobilinogen by intestinal bacteria, glucuronic acid is removed

Oxidized urobilinogen is excreted in stool as urobilin and stercobilin

A small portion is reabsorbed and recycled back into bile

Another small portion remains in blood and is filtered and excreted by kidney in urine, as urobilin.

6

Where is bilirubin converted to urobilinogen and urobilin?

Conversion to colorless urobilinogen occurs in the terminal ilium and colon

Oxidation to the yellowish urobilin occurs in urine

7

How does the hepatocyte take up bilirubin?

The hepatocyte takes up bilirubin across its basolateral membrane through an OATP and other unidentified mechanisms.

8

How does the hepatocyte process bilirubin?

The hepatocyte conjugates the bilirubin with one or two glucuronic acid residues and exports this conjugated form of bilirubin into the bile.

9

How is hemoglobin broken down?

Hemoglobin -> globin + heme

heme + O2 -> biliverdin (w/ heme oxygenase)

biliverdin + NADPH -> bilirubin (water insoluble)
- also releases NADP+
- uses biliverdin reductase

bilirubin complexed to albumin to go to liver

bilirubin -> bilirubin diglucoronide (water soluble)
- uses 2-UDP glucoronic acid, with glucoronyltransferase
- released via bile duct to intestines

bilirubin diglucoronide -> urobilinogen (bacteria)
- stercobilin excreted in feces
-urobilin excreted in kidneys

10

What is the van den Berg test?

measures blood levels of conjugated (water soluble) and unconjugated (water insoluble)

11

What happens to bilirubins initially in the small intestine?

Conjugated bilirubins are poorly reabsorbed, but are partly hydrolyzed back to unconjugated bilirubin by catalytic action of bacterial b glucuronidases

12

In the distal ileum and colon, anaerobic flora mediate further catabolism of bile pigments: 50% of conjugated bilirubin is converted into urobilinogen by intestinal bacteria. How is this process accomplished?

Hydrolysis of conjugated bilirubin to unconjugated bilirubin by bacterial b glucuronidases

Multistep hydrogenation (reduction) of unconjugated bilirubin to form colorless urobilinogens

Oxidation of unconjugated bilirubin to brown colored mesobilifuscins

5% of urobilinogen is excreted by kidney through urine

13

What is urobilinogens a collective term for?

3 group of 3 tetrapyrroles:
- Stercobilinogen
- Mesobilinogen
- Urobilinogen

14

What happens to the remaining 50% of conjugated bilirubin in intestines?

Remaining 50% of conjugated bilirubin is reabsorbed from intestine enters the entero-hepatic circulation and re-excreted as bile

A small fraction (2% - 5%) of urobilinogen enters the general circulation and excreted by kidney through urine. In urine, due to exposure to air, the urobilinogen is converted into urobilin by oxidation

15

What happens to the 3 urobilinogens in the lower GI tract?

In the lower intestinal tract, the 3 urobilinogens spontaneously oxidize to produce bile pigments, which are orange-brown color and are the major pigments of stool

16

What is the breakdown of total serum bilirubin? How is amount of unconjugated bilirubin determined?

Normally, total serum bilirubin ranges from 0.2-1.0 mg/dL.
Of this total, < 0.2 mg/dL is conjugated (water soluble).
The remainder of the total is unconjugated (water insoluble)

Total bilirubin- conjugated bilirubin = unconjugated bilirubin

17

What happens when serum bilirubin is elevated?

Elevations of serum bilirubin cause deposition in tissues and sclera of eyes- jaundice or icterus

Jaundice appears when bilirubin exceeds 2-3 mg/dL

18

What causes jaundice?

Liver must be functioning normally to eliminate the bilirubin produced daily

Causes of jaundice:
- excessive production of bilirubin
- reduced heaptocyte uptake
- impaired bilirubin conjugation
- impaired bile flow

19

What is high bilirubin in infants? What are the values?

In infants, bilirubin exceeding 15-20 mg/dL causes kernicterus

Kernicterus is a form of brain damage caused by excessive jaundice

The concentration of bilirubin in serum is so high that it can move out of the brain into brain tissue by crossing the fetal blood-brain barrier

20

What are 3 examples of hyperbilirubinemia?

1. Hemolytic anemia
increased blood unconjugated bilirubin
increased conjugated bilirubin released to bile duct

2. Hepatitis
increased unconjugated blood bilirubin
increased conjugated blood bilirubin

3. Biliary duct stone
increased unconjugated blood bilirubin
increased conjugated blood bilirubin

21

What is a cause of prehepatic jaundice? (simple)

Hemolysis

22

What are some causes of intrahepatic jaundice?

Infection
Chemical/drugs
Genetic errors - bilirubin metabolism
- Gilbert
- Crigler-Najjar
- Dubin-Johnson
- Rotor's
Genetic errors - specific proteins
- Wilson's
- alpha1 antitrypsin
Neonatal

23

What are some causes of posthepatic jaundice?

Intrahepatic bile ducts
- drugs
- primary biliary cirrhosis
- cholangitis

Extrahepatic bile ducts
- gall stones
- pancreatic tumor
- cholangiocarcinoma

24

What is the mechanism for prehepatic jaundice?

Prehepatic- excessive bilirubin presented to liver for metabolism and capable of excreting
- Overcomes ability of liver to clear.

Causes: hemolytic process

25

What are the lab findings for prehepatic jaundice?

Lab findings:
-↑ in serum unconjugated bilirubin.
-(Total bili usually does not exceed 5 mg/dL)
-Negative urine bilirubin
-Urinary urobilinogen ↑

26

What is the mechanism for hepatic jaundice?

Hepatic- abnormal hepatocyte function
-Cannot deal with normal load of bilirubin
Cause: enzyme mutation/impaired hepatocellular uptake (Gilbert’s syndrome)

27

What are the expected lab findings for hepatic jaundice? Why?

Serum total bilirubin < 3.0 mg/dL, primarily composed of unconjugated bili;
↑ urinary urobilinogen
Cause: enzyme mutation/defective conjugation (Crigler-Najjar type I syndrome)

Findings: serum unconjugated bili
often > 5.0 mg/dL; ↑ urinary urobilinogen
Cause: defective secretion by hepatocyte
(Dubin-Johnson syndrome)

Findings: ↑ serum conjugated bili
Cause: hepatitis with lowered conjugation or excretion

Findings: ↑ serum direct and indirect bili with
total levels of 5-10 mg/dL.

28

What is the mechanism for post-hepatic jaundice?

Posthepatic- impaired excretion of bilirubin
-Cause: mechanical obstruction of the flow of bile into the intestines due to gallstones or tumors

29

What are the expected lab findings for post-hepatic jaundice?

Findings:
↑ serum AND urine conjugated bilirubin
↓ level of urobilin/stercobilin in stool (clay-colored stools)
Negative urinary urobilinogen

30

See summary slide

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