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GI 2 > Heme Catabolism > Flashcards

Heme Catabolism Flashcards

1
Q

Approximately 6-7g of hemoglobin are synthesized each day to
replace heme lost through the normal turnover of red blood cells.
In the human body, ____ of the total iron is present as heme iron
in red blood cells.
During heme catabolism, the body has to deal with:
1) handling the_____ products of porphyrin ring cleavage
2) retention, safe mobilization, and re-utilization of____

A

~70%

hydrophobic

iron

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2
Q

Where does this occur:

Heme ring opening, heme –> biliverdin –>bilirubin

A

Macrophage

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3
Q

Albumin carries bilirubin from macrophage to liver in the ______

and Bilirubin is conjugated with glucuronic acid, excreted in the _______

A

blood

liver hepatocytes

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4
Q 
Gastrointestinal tract
Conjugated bilirubin is converted by bacteria, removal of
 glucuronic acid (i.e., deconjugated), conversion to\_\_\_\_\_\_
A

urobilinogen (more water soluble) that goes to kidneys

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5
Q

Kidney
Conversion of urobilinogen products to_____, excreted
in urine

A

urobilin

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6
Q

Understand basic bilirubin metabolism

A
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7
Q

Old RBC—> heme–> bilirubin (indirect) goes into plasma and takes a ride with ______ to the hepatocytes

In the liver______ will conjugate teh bilirubin

Bilirubin can go what to _____ or ______

A

albumin

bilirubine glurornice

to urine (as urobilin)

to bile duct

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8
Q

What makes poop brown

A

bacteria; stercobilin

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9
Q

Heme is degraded in a series of reactions to produce ______ which is normally
excreted into bile by the liver. Jaundice or icterus results from accumulation of
elevated bilirubin in the skin and sclera, imparting a yellow color to these tissues.
Inherited disorders of bilirubin metabolism lead to_______.

A

bilirubin

hyperbilirubinemia

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10
Q

Approximately 80% of heme catabolism occurs from _______ and 20% coming from ________ and various cytochromes in nonerythroid tissues. RBCs have an average lifetime of 120 days, after which they are taken up by macrophages of the:

A

senescent erythrocytes,

turnover of immature red blood cells (RBCs)

liver and spleen.

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11
Q
A
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12
Q

Bilirubin, an orange pigment derived from the degradation of heme proteins, is a
potentially toxic waste product that is generally harmless because

A

of binding to serum albumin. However, there are several clinical conditions involving abnormal bilirubin metabolism.

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13
Q

The ferroprotoporphyrin IX ring is selectively cleaved at the - methene bridge. The first step is catalyzed by______ requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR).

A

heme oxygenase
(HO-1)

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14
Q

2nd step heme catabolism the: nonenzymatic oxidation by molecular oxygen with the elimination of CO (only known reaction in human tissues and cells that produces(CO) as a by-product of metabolism). The release of___ occurs after addition of electrons and the resulting green pigment
is_____

A

iron

biliverdin

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15
Q

Endogenous compounds are toxic in their free form:
Fe2+/ 3+ –>bound by___
CO –> bound by____

A

ferritin

hemoglobin

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16
Q

Biliveridin to bilirubin via:

A

biliverdin reductase, which can
use either NADH or NADPH for activity. Bilirubin is less polar (antioxidant during fetal)

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17
Q

Transports bilirubin, keeps in solute takes to liver from spleen and Kupfner cells

A

albumin

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18
Q

Although tightly bound to albumin, bilirubin is rapidly removed from the circulation by ____ Bilirubin dissociates from albumin before entering the
________

A

the liver.

hepatocyte

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19
Q

Once inside the hepatocyte, bilirubin is kept in solution through interactions with cytosolic proteins, termed______. This inhibits the_____ of bilirubin back
into the circulation and also represents a form of temporary storage within the hepatocyte.

A

ligandins

efflux

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20
Q

______is the major conjugating group and the reaction is catalyzed by a specific form of uridine diphosphate glucuronosyltransferase (UGT1A1).

A

Glucuronic acid

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21
Q

_____is specific for bilirubin and is primarily located in the endoplasmic reticulum of the hepatocyte. Either one or two glucuronic acid moieties of UDP-glucuronic acid are transferred onto bilirubin yielding the mono- (BMG) or diglucuronide (BDG) species, respectivel

A

UGT1A1

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22
Q

mono- (BMG) or diglucuronide (BDG)
smay also bind to

A

ligandins

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23
Q

_____ is essential for bilirubin excretion and this process appears to be energy-dependent and shared with other organic anions, except _____

A

Conjugation

bile salts.

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24
Q

Has been identified in canalicular membranes and is involved in bilirubin excretion

A

An ATP-dependent multiorganic anion
transporter (MOAT)

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25
Q

Bilirubin reaches the intestinal tract mainly conjugated and is not substantially readsorbed. Rather, bilirubin is degraded by intestinal bacteria into a series of______ products.

A

urobilinogen

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26
Q

Urobilinogens are present in the______ state and it is not known whether this precedes or follows degradation of bilirubin to urobilinogens.

A

deconjugated

27
Q

Clinical Lab Test for Serum Bilirubin

A

Van Den Bergh Assay (allows for direct quantification)

28
Q

Only the water soluble, conjugated bilirubin reacts
rapidly in this assay,yields a value for_____
bilirubin. Unconjugated, water insoluble bilirubin
reacts slowly, not detected unless you perform the assay in:

A

direct

Methonal

29
Q

What type of assay do you conduct to get total bilirubin

A

in methonal, both conjucated and unconjucated are solbule

30
Q

How do you calculate Indirect bilirubin?

A

Total Bili - Direct (conjugated)

31
Q

Four causes of Unconjucated hyperbilirubenemia

A

Neonatal jaundice

Crgler-Najjar Type I

Crigler-Najjar Type II

Gilbert Syndrome

Hemolytic

Hepatocellular

32
Q

What causes direct or conjucated hyperbilirubeninma

A

Dubin-Johnson

Rotor syndrome

Obstructive issues

33
Q

Neonatal Jaundice

Serum bilirubin is predominantly unconjugated. If untreated, high bilirubin levels
can damage regions of the brain, such as the
________, involved in controlling muscle movement.

A

basal ganglia (yellow discoloration)

34
Q

_______is a specific form of brain damage (“bilirubin encephalopathy”) due to hyperbilirubinemia, causing athetoid (writhing) cerebral palsy and often
hearing loss.

A

Kernicterus

35
Q

Tx of neonatal jaundice

A

phototherapy with light in the blue-green spectrum (430-490 nm; bilirubin can be excreted in bile
without conjugation.

36
Q

What do teh Hepatic bilirubin UDP glucornosyltransfersase levles look for:

Criger-Najjar I

Crigler-Najjar II

Gilbert

A

Criger-Najjar I; absent!

Crigler-Najjar II: markedly reduced <20%

Gilbert: reduced ~30%

37
Q

All three syndromes are related to disorders in UGT1A1 expression, which results in more Unconjugated Bilirubin, and are listed (left to right) in decreasing order of severity.

A

Crigler-Najjar I (BAD!)

Crigler-Najjar II (not great)

Gilbert; more common

38
Q

Defects of bilirubin secretion: both syndromes are inherited, but relatively mild.
_____ is thought to be a defect in organic ion transport (MOAT defect).
_____ is rare and not characterized at the molecular level.

A

Dubin-Johnson

Rotor syndrome

39
Q

Dublin Johson and Rotor are both _____hyperbilirubeinmia

Whats a way to tell them apart?

A

Conjucated

Dublin; defect in MOAT and you have grossly BLACK liver

Rotor is rare, no molecular difference

40
Q

Inability of hepatocytes to secrete conjugated bilirubin into the bile canaliculi after it has been formed. Conjugated bilirubin returns to the blood.

A

Conjucated hyperbilirubenemia

41
Q

Excessive erythrocyte destruction results in the formation of bilirubin in amounts exceeding the conjugating ability of the liver and hence its excretion
into the bile. Free bilirubin increases in plasma as a result.

A

Hemolytic ; causes jaundice; Indrect hyperbilirubenima

42
Q

Caused by partial or complete blocking of the bile ducts. Conjugated bilirubin is prevented from being excreted into the intestine and consequently appears in increased amounts in the plasma

A

Obstructive–> Increased DIRECT

43
Q

Damage to the liver by toxins, poisons, cardiac failure,
or acute or chronic disease impairs the liver’s capacity to conjugate circulating bilirubin and hence excrete it.

A

Hepatocellular; increased Indirect/unconjucated

44
Q

Where do we get cholesterol, why is it important?

A

from diet or made de novo

key for bile acids, steriod hormones, Vit D, lipid bylaters

45
Q

Bile acids are synthesized from______ in the liver.
Bile acids are secreted into _____, which are specialized channels formed by adjacent hepatocytes.

A

cholesterol

bile canaliculi

46
Q

specialized channels formed by adjacent hepatocytes.

A

bile canaliculi

47
Q

Bile acids are carried to the GB for storage and then to the small intestine where they are_____.
Bile acids act as_____ agents to prepare dietary
triglycerides for hydrolysis by pancreatic lipase, & they
facilitate absorption of ____

A

excreted

emulsifying

fat-soluble vitamins

48
Q

Cholesterol is Excreted Primarily as

A

Bile Acids

49
Q

Bile acids are synthesized from _____ in the liver. Most abundant bile acids are derivatives of ______

A

cholesterol

cholic acid.

50
Q

Bile acids represent a major mechanism
by which cholesterol is excreted: the carbon skeleton of cholesterol is notdegraded (oxidized to CO2 and H2O) in humans but

A

is excreted in bile as
free cholesterol and as bile acids

51
Q

Cholic acid and Chendeoxycholic acid are both:

where are they made?

A

Primary bile acids

made in hepatocytes from cholesterol

52
Q

deoxycholic acid & lithocholic acid are:

How are they made?

A

secondary bile acids

made when primary are converted to secondary by gut bacteria

53
Q

Primary and secondary bile acids are reabsorbed by the intestine (lower ileum) into portal blood, and taken up by hepatocytes where they are conjugated to
_____ or ______, forming bile salts

A

glycine or taurine

54
Q

Why is conjucation of bile acids important?

A

it converts the bile acids into molecules (i.e., bile salts) with a lower pKa value. The lower
pKa of bile salts = more soluble in the small intestine

55
Q

Bile acids act as emulsifying agents to prepare dietary
triacylglycerols for hydrolysis by_____They alsoacilitate the absorption of ____ from the intestine.

A

pancreatic lipase.

fat-soluble vitamins (vitamin D)

56
Q

Bile acids reabsorbed and returned to liver for

A

recycling (>95% efficiency)

(12-32g per day)

57
Q

The capacity of the liver to produce bile acids is insufficient to meet physiological demands,

so the body relies on an efficient _____that carries bile acids from the intestine back to the liver

A

enterohepatic circulation

58
Q
A
59
Q

Major mechanism of cholesterol excreation

A

feces: 0.2–0.4 g/day

60
Q

1) elevated concentration of LDL in the plasma
2) deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
3) inheritance as an autosomal dominant trait with a gene dosage effect (homozygotes are more severely affected than heterozygotes)

A

Familial Hypercholesterolemia (FH)

61
Q

Defect in FH is a mutation in the gene encoding the

A

LDL receptor.

62
Q

Heterozygotes of FH number 1 in 500 persons, placing FH among the most common inborn errors of metabolism. Heterozygotes have ____elevations
in plasma cholesterol from birth.

A

twofold

63
Q

1) LDL receptor limits LDL production
by enhancing the removal of the
precursor, _____from the circulation.
2) LDL receptor enhances LDL____ by mediating cellular uptake of LDL (apo B-100).

A

IDL (B-100, apo E  higher affinity for LDL receptor),

degradation

64
Q

How do you tx FH?

A

stimulating the single normal LDL receptor

Bile acid binding resins (cholestyramine and colestipol) –bind biles acids in the intestinal lumen, preventing their absorption from the ileum

2) HMG-CoA reductase inhibitors (statins

Diet low in cholesterol and fats

GI 2 (12 decks)

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