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FHB Exam 3 > Metabolism: Heme > Flashcards

Metabolism: Heme Flashcards

1
Q

What tissues have the highest rates of heme biosynthesis?

A

liver => cytochromes

bone marrow => hemoglobin

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2
Q

Describe the rate limiting reaction of heme synthesis.

A

First step; occurs in mitochondria
succinyl-CoA + Glycine => ALA (d-aminolevullinic acid)
via ALA synthase

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3
Q

Differentiate between porphyrinogens and porphyrins.

A

porphyrinogen - no double bonds; colorless;

porphyrins - double bonds; colored, fluorescent, photodegradable

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4
Q

How is ALA synthase regulated?

A

allosteric negative feedback by heme (works on ALAS1 in the liver)

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5
Q

Describe the 2 kinds of ALAS.

A 
ALAS1 = all tissues
ALAS2 = bone marrow erythroid cells
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6
Q

Define porphyrias.

A

diseases caused by partial deficiency of one of the enzymes involved in heme biosynthesis

  • caused by increased heme metabolic intermediates
  • typically 50% enzyme activity is present (haploinsufficiency)
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7
Q

Describe the inheritance pattern of acute intermittent porphyria.

A
  • autosomal dominant

- incomplete penetrance (most people who inherit the trait never have symptoms)

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8
Q

What are some symptoms of acute intermittent porphyria?

A
  • nerve damage
  • acute attacks of abdominal pain
  • tachycardia
  • HTN
  • muscle weakness
  • tremors
  • seizures
  • agitation/hallucinations
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9
Q

What is the etiology of acute intermittent porphyria?

A

deficiency in porphobilinogen deaminase enzyme

  • leads to increased ALA and PBG
  • leads to decreased heme synthesis
  • diminished feedback inhibition of heme on ALAS1
  • increased ALAS1 activity => more ALA and PBG formed => exacerbation
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10
Q

What is the treatment of acute intermittent porphyria?

A
  • low glucose diet, OH, steroids, and other drugs can increase ALAS and exacerbate the disease
  • tx: glucose infusion, IV heme to suppress ALAS
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11
Q

What other porphyrias exhibit acute attacks like acute intermittent porphyria?

A
  • variegate
  • hereditary coproporphyria

==> causes skin sensitivity

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12
Q

Describe the inheritance pattern of variegate porphyria.

A
  • autosomal dominant
  • incomplete penetrance
  • founder effect of South African whites
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13
Q

What is the etiology of variegate porphyria?

A
  • deficiency in protoporphyrinogen oxidase
  • increased levels of protophorphyrinogen III and coprotoporphyrinogen III in liver
  • reduced heme synthesis
  • increased ALAS activity
  • increased ALA and PBG
  • proto and coproto deposits in the skin => converted to porphyrins by light => further photodegradation => O2 => tissue degradation
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14
Q

What are some symptoms of variegate porphyria?

A

blisters

skin lesions

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15
Q

How does lead affect heme synthesis?

A
  • inhibits 3 enzymes

- elevated ALA, coproporphryinogen, protoporphyrinogen III

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16
Q

Which 3 enzymes are inhibited by lead?

A
  • ALA dehydratase
  • coproporphyrinogen oxidase
  • ferrochetalase
17
Q

What is the diagnostic marker for lead poisoning?

A

increased levels of protoporphyrinogen in RBCs

18
Q

Where does heme catabolism take place?

A

RBCs are phagocytized by RES cells (macrophages in spleen, liver, bone marrow)

19
Q

Tracks the steps in heme catabolism leading to the formation of unconjugated bilirubin.

A
  1. hemoglobin => heme + globin
  2. heme => Fe (reutilized) + biliverdin
  3. biliverdin => unconjugated bilirubin
  4. unconjugated bilirubin-albumin => liver, active absorption
20
Q

Describe the reaction by which bilirubin is conjugated.

A

2 glucuronic acids (UDP-glucuronate) are attached to bilirubin

21
Q

What makes urine yellow?

A

urobilin

22
Q

What is the cause of hyperbilirubinemia?

A
  • > 1mg/dL bilirubin in serum
  • either conjugated or unconjugated accumulation
  • diffuses into tissue => yellow
  • jaundice (>2-2.5 mg/dL)
23
Q

What are clinical consequences of hyperbilirubinemia?

A
  • conjugated is benign

- unconjugated => toxic encephalopathy after > 25 mg/dL (kernicterus)

24
Q

List 4 causes of jaundice.

A
  • hemolysis
  • biliary obstruction
  • hepatitis/cirrhosis
  • neonatal
25
Q

How does hemolysis cause jaundice?

A
  • increased RBC destruction => releases unconjugated bilirubin in blood
26
Q

How does biliary obstruction lead to jaundice?

A
  • conjugated bilirubin not delivered to intestines => piles up in blood
  • dark urine b/c conjugated bilirubins present in urine
  • white feces b/c not enough stercobilin
27
Q

How does hepatitis/cirrhosis cause jaundice?

A
  • decrease in conjugation and excretion of bilirubin
  • increased unconjugated bilirubin
  • lack of stercobilin in bilirubin and urobilin in urine
  • mixed hyperbilirubinemia
28
Q

Why do neonates sometimes have jaundice?

A
  • fragile RBCs
  • immature hepatic system leads to decreased conjugation, excretion, and uptake
  • increased unconjugated in blood
  • can cause kernicterus
29
Q

How do you treat icteric neonates?

A
  • blue light converts unconjugated bilirubin to more soluble, and BBB-impermeable isoforms
  • excreted properly
30
Q

How can porphyrinogens become porphyrins?

A

light

31
Q

Relate heme degradation to bruising.

A
  1. initially bruises are black and blue b/c heme has lost oxygen
  2. heme => biliverdin = green
  3. biliverdin => bilirubin = yellow
32
Q

Why is unconjugated bilirubin dangerous when > 25 mg/dL in serum?

A

b/c binding capacity to albumin is 25 mg/dL

  • as long as it is bound to albumin, it cannot get to the brain
  • once bilirubin > albumin, free unconjugated bilirubin can enter the brain

FHB Exam 3 (23 decks)

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