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Physiology Metabolism > Metabolism 12: Heme Metabolism > Flashcards

Metabolism 12: Heme Metabolism Flashcards

1
Q

Which tissues have the highest rate of heme synthesis and where do they incorporate it into?

A

Bone Marrow: hemoglobin incorporation in erythrocytes

Liver: Cytochrome incorporation (P-450 enzymes)

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2
Q

What enzyme is rate limiting and highly regulated in heme biosynthesis?

A

ALA Synthase (1st step)

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3
Q

What reaction does ALA synthase catalyze?

A

Succinyl CoA + Glycine -> ALA

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4
Q

What’s the difference between porphyrinogen and porphyrins?

A

Porphyrinogen: No double bonds at bridging carbons, colorless
Porphyrin: double bods at bridging carbons, colored

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5
Q

How can porphyrinogens be converted to porphyrins?

A

Non-enzymatically oxidized by light

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6
Q

What are the two ALA Synthases and where are tehy present in?

A

ALAS1: all tissues
ALAS2: bone marrow erythroid cell

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7
Q

How does regulation of heme biosynthesis differ between bone marrow and liver?

A

Liver: heme inhibits its own synthesis by decreasing ALAS1 activity

Bone Marrow: ALAS2: not regulated by heme

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8
Q

What is the sequence of heme synthesis?

A

Succinyl CoA + Glycine -> ALA ->Porphobilinogen -> Hydroxymethylbilane -> Uroprophyrinogen III -> Coproporphyrinogen III -> Protoporphyrinogen III -> Protoporphyrin III -> Heme

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9
Q

What is porphyria?

A

disease caused by partial deficiency of one of the enzymes in heme biosynthesis. Sx caused by increase in metabolic intermediates rather than lack of heme production

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10
Q

What enzyme is deficient in acute intermittent porphyria?

A

Porphobilinogen deaminase. Leads to increased levels of ALA and porphobilinogen and lower concentration of heme in liver

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11
Q

How does the lower rate of heme synthesis affect pts with acute intermittent porphyria?

A

Lower heme production reduces the feedback inhibition o ALA Synthase -> leads to more ALA and PBG to exacerbate the disease

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12
Q

What is the treatment for acute intermittent porphyria?

A

Glucose infusion and IV heme to suppress ALA Synthase

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13
Q

What is deficient in variegate porphyria?

A

Deficient in protoporphyrinogen oxidase -> leads to increased levels of protoporphyrinogen III and coproporphyrinogen III in liver

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14
Q

Why does blistering and skin lesions occur with variegate porphyria?

A

protoporphyrinogen and coproporphyrinogen are deposited in skin and converted to porphyrins by sunlight. The porphyrins are then degraded by light and generate tissue damaging singlet oxygen

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15
Q

What is seen in both variegate porphyria and acute intermittent porphyria?

A

Reduce heme syntehsis leading to increased ALA Synthase activity leading to increased ALA and PBG

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16
Q

What enzymes are inhibited in lead poisoning?

A

ALA Dehydratase, coproporphyrinogen oxidase, ferrochelatase

17
Q

What is elevated with lead poisoning?

A

ALA, coproporphyrinogen, protoporphyrin III

18
Q

How is erythrocyte destroyed?

A

Taken up by phagocytic cells of the reticuloendothelial system and destroyed

19
Q

What is generated with hemoglobin degradation?

A

Heme(Fe and bilirubin) and globin(free amino acids)

20
Q

What is the degraded product of heme degradation?

A

Unconjugated bilirubin (insoluble)

21
Q

How is unconjugated bilirubin delivered to the liveR?

A

Carried in plasma complexed with albumin and then taken up by the liver via active transport for conjugation

22
Q

How does the liver conjugate bilirubin?

A

Attaches 2 glucuronic acid groups to the unconjugated bilirubin

23
Q

What happens to the conjugated bilirubin formed in the liver?

A

It is soluble and is secreted actively into bile canaliculus

24
Q

What is another name for conjugated bilirubin?

A

bilirubin diglucuronide

25
Q

What stool its brown color?

A

Presence of stercobilins which is generated when conjugated bilirubin in the intestine is digested by bacterial flora and then oxidized

26
Q

What gives urine its yellow color?

A

Urobilin: oxidized form of urobilinogen

27
Q

What is hyperbilirubinemia?

A

Elevated bilirubin in serum (>1 mg/dL)

Both unconjugated and conjugated

28
Q

How does bilirubinemia cause jaundice?

A

Elevated bilirubin diffuses into tissue and makes them yellow.

29
Q

When is jaundice detectable in the eye?

A

Serum bilirubin >2-2.5mg/dl

30
Q

What are the clinical significances of conjugated/unconjugated bilirubinemia?

A

Conjugated Hyperbilirubinemia: benign

Unconjugated Hyperbilirubinemia: benign when <25mg/dL (Albumin binding capacity)

31
Q

What happens when unconjugated hyperbilirubinemia exceeds 25 mg/dL?

A

free unconjugated bilirubin can enter brain and cause toxic encephalopathy (kernicterus)

32
Q

What causes jaundice?

A

Hemolysis
Biliary Obstruction
Hepatitis/Cirrhosis

33
Q

What does hemolysis result in?

A

increased blood unconjugated bilirubin

34
Q

What does biliary obstruciton lead to?

A

increased blood conjugated bilirubin -> dark urine

Chalky white stool due to lack of stercobilins

35
Q

How does hepatitis/cirrhosis cause jaundice?

A

Liver damage leads to decreased conjugation and thus decreased excretion of bilirubin

Mixed hyperbilirubinemia

36
Q

What causes neonatal physiological jaundice?

A

fragile erythrocytes

immature hepatic system- decreased uptake, conjugation, and excretion of bilirubin

37
Q

What results in neonatal physiological jaundice?

A

increased blood unconjugated bilirubin

If too high (>15mg/dl) can lead to kernicterus

38
Q

What is the treatment for neonatal physiological jaundice?

A

Blue light: convert insoluble and BBB permeable unconjugated bilirubin to isomers that are soluble and impermeable to BBB -> excreted in urine or bile

Physiology Metabolism (11 decks)

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