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Heme and iron metabolism Flashcards

1
Q

What is heme?

A

Prosthetic group of iron and porphyrin

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2
Q

What is porphyrin?

A

Ring-like molecule w/ different side groups (methyl/vinyl/propionic) and Fe at the center

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3
Q

Function of Fe

A

Bind O2 and accept/donate electrons to facilitate redox rxn

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4
Q

Heme functions

A

Hemoglobin (RBC) and myoglobin (muscle) for O2 binding

Cytochrome for electron transfers (detoxification)

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5
Q

Where does heme synthesis take place?

A

Occurs in all cells but mainly in liver and erythroid cells (marrow - 85%)

Occurs in cytoplasm/mitochondria

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6
Q

Steps of heme synthesis (hint: condensation rxns -> formation of ring structure -> conversion of side grps -> insertion)

A

1) Succinyl-CoA + glycine -> ALA by ALA synthase (catalyst for rxn)
- irreversible
- inhibited by heme and Fe (neg feedback)
- req pyridoxal phosphate (vit B6)
- occurs in mitochondria

2) 2 ALA -> porphobilinogen (PBG-building block for ring structure) by ALA dehydratase (catalyst)
- inhibited by heavy metal ions (lead)
- condensation rxn
- occurs in cytosol

3) 4 PBG -> hydroxymethylbilane by PBG deaminase (removes amino grps in PBG)
- condensation rxn
- occurs in cytosol

4) Hydroxymethylbilane -> uroporphyrinogen III by uroporphyrinogen cosynthase
- forms ring structure needed to chelate Fe

5) Uroporphyrinogen III -> coproporphyrinogen III by uroporphyrinogen decarboxylase
- removal of carboxyl groups to form methyl groups
- occurs in cytosol

6) Coproporphyrinogen III -> protoporphyrinogen IX by coproporphyrinogen oxidase/porphyrinogen oxidase
- oxidative decarboxylation
- conversion of propanoic acid side grp to 2 vinyl side grp
- occurs in mitochondria

7) Protoporphyrinogen IX -> heme by ferrochelatase
- insertion of Fe2+ to form heme
- inhibited by heavy metal ions (lead) -> leads to decreased heme synthesis causing anaemia
- occurs in mitochondria

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7
Q

How is synthesis of heme regulated?

A

Via 2 isoforms of ALA synthase, ALAS1 and ALAS2

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8
Q

How does ALAS1 work?

A

Stimulated by drugs/toxins -> increase heme for cytochromes for detoxification

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9
Q

Where does ALAS1 fn?

A

Liver

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10
Q

How does ALAS2 work?

A

Stimulated by hypoxia and erythropoietin -> increase heme for hemoglobin (RBC)

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11
Q

Where does ALAS2 fn?

A

Bone marrow

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12
Q

What inhibits ALAS1 and ALAS2?

A

Heme/Fe via neg feedback loop

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13
Q

What can go wrong with heme synthesis (genetic)?

A

Porphyrias - deficiencies in heme synthesis pathway

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14
Q

2 impt types of porphyrias and what they inhibit

A

Acute intermittent porphyria
- deficient porphobilinogen deaminase -> prevent condensation of PBG to hydroxymethylbilane

Porphyria cutanea tarda
- most common
- deficient uroporphyrinogen decarboxylase -> inhibit conversion of uroporphyrinogen III to coproporphyrinogen III

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15
Q

Presentation of porphyria (due to accumulation of PBG)

A

Abdominal pain

Neuropsychiatric symptoms

Urine that darkens on exposure

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16
Q

Presentation of porphyria (due to accumulation of hydroxymethylbilane/porphyrin structures)

A

Photosensitivity w/ skin lesions
Red urine

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17
Q

What can go wrong with heme synthesis (acquired)?

A

Heavy metal poisoning (lead)

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18
Q

How is heavy metal poisoning acquired?

A

Exposure to source of lead like paint and ceramics

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19
Q

How does heavy metal poisoning affect heme synthesis pathway?

A

Inhibit ALA dehydratase and ferrochelatase -> reduce heme -> anemia

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20
Q

Presentation of heavy metal poisoning

A

Bluish coloration at gum line (Burton’s line)

Pallor

Abdominal pain

Neuropathy

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21
Q

What can kidney excrete?

A

Soluble cmpds

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22
Q

Major source of heme breakdown

A

Senescent RBCs (old RBCs, ~120 days)

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23
Q

Flow of heme breakdown

A

Macrophage -> liver-> gut -> kidney/reabsorbed back to liver

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24
Q

Heme breakdown (macrophage)

A

Heme -> biliverdin (greenish) by heme oxygenase
- breakdown of ring
- oxidation of Fe2+ to Fe3+

Biliverdin -> bilirubin (yellowish) by biliverdin reductase
- bilirubin is insoluble and is bound to albumin in blood
- increase -> cross BBB -> toxic to developing brain

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25
Q

Heme breakdown (liver)

A

Bilirubin -> bilirubin diglucoronide (conjugated bilirubin) by UDP glucuronosyl transferase (UGT)
- increase solubility of bilirubin
- active transport into bile caniculi as bile; enter gut

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26
Q

Heme breakdown (gut)

A

Conjugated bilirubin -> urobilinogen by bacterial removal of glucuronic acid
- urobilinogen -> oxidised in gut to stercobilin (cause brownish colouration of stools)
- urobilinogen partly reabsorbed back to liver (enterohepatic circulation) and blood

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27
Q

Heme breakdown (blood)

A

Urobilinogen filtered through kidneys and excreted in urine
- urobilinogen in urine oxidised to urobilin -> yellowish colouration of urine

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28
Q

Is unconjugated bilirubin soluble?

A

No

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29
Q

What is hyperbilirubinemia?

A

Total bilirubin (unconjugated + conjugated) > 1.2 mg/dL

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30
Q

How is hyperbilirubinemia detected?

A

Jaundice (>2.5-3 mg/dL)

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31
Q

Classification of hyperbilirubinemia and what it means?

A

Prehepatic -> excess bilirubin production

Hepatic -> defective processing/excretion

Obstructive -> block in excretion

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32
Q

Causes of prehepatic hyperbilirubinemia

A

Increased breakdown in RBC (hemolysis) -> increased bilirubin exceeding liver capacity

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33
Q

How does hemolysis cause prehepatic hyperbilirubinemia?

A

Hemolysis -> increased unconjugated bilirubin -> increased amt of conjugated bilirubin in bile (but conjugated bilirubin conc in blood is normal as no blockage preventing it from entering gut) -> increased conversion to urobilinogen by bacteria -> increased reabsorption of urobilinogen to blood -> increased filtered urobilinogen thru kidney into urine

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34
Q

Characteristics of prehepatic hyperbilirubinemia

A

Increased unconjugated bilirubin

Normal conjugated bilirubin

Increased urobilinogen (in urine)
- detect hyperbilirubinemia

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35
Q

Conditions that can cause hemolysis

A

G6PD/PK deficiency, malaria

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36
Q

How does severe hemolysis present

A

Dark urine (kopi-o colour)

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37
Q

Why does severe hemolysis cause dark urine?

A

Severe hemolysis -> increased free hemoglobin -> excreted n urine (hemoglobinuria) -> dark urine

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38
Q

Causes of hepatic hyperbilirubinemia

A

Dysfunction of liver cells -> defects in reabsorption of urobilinogen, transport of conjugated bilirubin and conjugation of bilirubin
- combination/degree of defects depends on the cause of liver problem and stage of liver dysfunction

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39
Q

Changes in indices caused by disrupted reabsorption of urobilinogen

A

Increased urinary urobilinogen
- due to increased levels of circulating urobilinogen filtered thru kidneys

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40
Q

Changes in indices caused by defective transport of conjugated bilirubin

A

Increased conjugated bilirubin

Decreased urinary urobilinogen
- due to accumulation of conjugated bilirubin in blood, less in gut -> urobilinogen decrease -> amt of reabsorbed urobilinogen decrease -> less filtration by kidney

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41
Q

Changes in indices caused by defective conjugation of bilirubin

A

Increased unconjugated bilirubin

Decreased conjugated bilirubin

Decreased urobilinogen
- decreased stercobilin -> pale stools (severe)

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42
Q

Causes of defects in bilirubin conjugation

A

Genetic -> disrupt fn of UDP glucuronosyltransferase
- Gilbert’s syndrome (benign) (autosomal recessive)
- Crigler-Najjar (possibly severe)

Hormonal/drugs
- thyroxine
- estradiol contraceptive

Physiological
- neonatal immaturity

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43
Q

Causes of defective bilirubin excretion

A

Genetic -> defective transporter
- Dubin-Johnson syndrome (rare)
- Rotor syndrome (rare)

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44
Q

What does Dubin-Johnson syndrome cause?

A

Mutation in MRP2 transporter for excretion of conjugated bilirubin

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45
Q

Trait of Dubin-Johnson syndrome

A

Black liver

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46
Q

What is Rotor syndrome?

A

Mutation in SLCO I B I/B3 transporter

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47
Q

What causes jaundice due to mixed defects?

A

Hepatocyte dysfunction caused by infection, toxicity or autoimmune

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48
Q

Pathophysiology of early dysfunction

A

Defect in reabsorption

Decreased excretion of conjugated bilirubin

49
Q

Clinical findings during early dysfunction

A

Increased urobilinogen
(explanation: less reabsorbed -> more circulating -> more filtered by kidney -> increased urinary urobilinogen)

Increased conjugated bilirubin
(explanation: decreased excretion -> initial rise in conjugated bilirubin in blood)

50
Q

(Pathophysio) What predominates when hepatocellular dysfunction worsens?

A

Defect in excretion of conjugated bilirubin

51
Q

Clinical findings of progressive hepatocellular dysfunction

A

Increased unconjugated bilirubin

Increased conjugated bilirubin

Conjugated bilirubin in urine

Decreased urobilinogen

Decreased stercobilin -> pale stools
(explanation: amt of conjugated bilirubin increase significantly -> backflow -> smaller rise in unconjugated bilirubin -> significantly less conjugated bilirubin reaches gut -> decreased urobilinogen -> decreased stercobilin)

52
Q

What causes obstructive jaundice?

A

Obstruction to bile duct from different etiologies

53
Q

Classification of obstructive jaundice

A

Acquired

Congenital

54
Q

Examples of acquired obstructive jaundice

A

Bile duct stones

Carcinoma

Infection

55
Q

Examples of congenital obstructive jaundice

A

Cysts

Atresia

56
Q

Clinical findings of obstructive jaundice

A

Increased conjugated bilirubin -> dark urine

Conjugated bilirubin in urine

Decreased urobilinogen

Decreased stercobilin -> pale stools

Increased unconjugated bilirubin (late)

57
Q

What to suspect in excess free hemoglobin and the biochemical parameter changes?

A

Prehepatic jaundice

Decreased haptoglobin
(explanation: Hemolysis of RBC -> release free Hb -> haptoglobin bind to Hb to form complex -> complex removed by macrophages -> decreased haptoglobin)

58
Q

Biochemical parameter changes during liver damage

A

Increased AST

Increased ALT

59
Q

Biochemical parameter changes during liver dysfunction

A

Decreased albumin

Increased PT/PTT

60
Q

Biochemical parameter changes during liver obstruction

A

Increased ALP

Increased GGT

61
Q

Causes of neonatal jaundice

A

Increased RBC lysis

Decreased bilirubin conjugation

(both result in increased unconjugated bilirubin -> can’t be excreted)

62
Q

Risk of high levels of unconjugated bilirubin to neonates

A

Cross immature BBB -> neurological damage (kernicterus)

63
Q

Risk factors of neonatal jaundice

A

Blood group incompatibility

G6PD deficiency

Prematurity (BBB not fully formed/ liver can’t conjugate bilirubin)

Low albumin

64
Q

Which babies have higher risk of hyperbilirubinemia?

A

Chinese (Gilbert’s syndrome)

65
Q

What is Gilbert’s syndrome?

A

Mutation in UDP glucuronosyl-transferase (UGT)

66
Q

Treatment for neonatal jaundice and their effects

A

Mild: blue-light phototherapy -> increase excretion of bilirubin

Severe: exchange transfusion -> rapidly decrease bilirubin

67
Q

How does blue-light phototherapy work?

A

Converts insoluble bilirubin to more soluble isomer (rotation ard double bonds)

68
Q

What happens to heme?

A

Most used to make hemoglobin

69
Q

What is hemoglobin?

A

Tetrameric protein made from 2 alpha and 2 beta subunits, each subunit contains heme grp for carrying O2

70
Q

2 states of hemoglobin

A

Deoxy Hb
- tissue
- low O2
- high CO2

Oxy Hb
- lung
- high O2
- low CO2

71
Q

Conditions for conversion of deoxy-Hb to oxy-Hb

A

High O2

Low H+

72
Q

Conditions for conversion of oxy-Hb to deoxy-Hb

A

Low O2

High H+

Stimulated allosterically by 2,3-BPG

73
Q

What type of globins is hemoglobin synthesised from?

A

Alpha type - zeta and alpha

Beta type - epsilon, gamma, beta and delta

74
Q

Predominant forms of hemoglobin during development and their subunits

A

Initial: Hb gower (zeta2epsilon2)

Next: HbF (alpha2gamma2)

Birth: HbA (alpha2beta2)

75
Q

Predominant forms of hemoglobin in adults

A

HbA (alpha2beta2) - 90%

HbA2 (alpha2delta2)

HbF (alpha2gamma2)

76
Q

Organisation of alpha and beta type globins

A

Organised in gene clusters on diff chromosomes -> 2 copies of alpha globin (chromosome 16) and 1 copy of beta globin (chromosome 11)

77
Q

What can go wrong in hemoglobin synthesis?

A

Thalassemia (genetic)

78
Q

What is thalassemia?

A

Defect in synthesis of alpha or beta globin genes
- defect in alpha genes -> alpha thalassemia
- defect in beta genes -> beta thalassemia

79
Q

What kind of genetic disorder is thalassemia?

A

Autosomal recessive

80
Q

Is thalassemia common in SEA?

A

Yes

81
Q

Presentation of thalassemia

A

Hemolysis
- splenomegaly

Anemia
-hepatomegaly (due to compensation by erythropoiesis in liver)
- expansion marrow including head (due to compensation by erythropoiesis in bone marrow)

Release of heme
- prehepatic jaundice

Release of Fe
- organ damage

82
Q

How does alpha and beta thalassemia arise?

A

Mutation of alpha and beta globin gene respectively

83
Q

How many copies of alpha globin gene does a person have?

A

4 copies (2 per chromosome)

84
Q

How is the severity of alpha thalassemia determined?

A

The number of defective copies of alpha globin gene
- 1 defective copy -> asymptomatic
- 2 defective copies -> mild symptoms (trait)
- 3 defective copies -> HbH disease (severe)
- 4 defective copies -> lethal

85
Q

What happens when there is less alpha globin?

A

Less alpha globin to combine with
- less HbA (alpha2beta2)
- more gamma4 (self-associate)
- more beta4 (self-associate) -> unstable -> precipitate -> hemolysis

86
Q

How many copies of beta globin gene does a person have?

A

2 copies per individual

87
Q

How is the severity of beta thalassemia determined?

A

The number of defective copies of beta globin gene
- 1 defective copy -> minor -> mild symptoms
- 2 defective copy -> major -> severe symptoms

88
Q

What happens when there is less beta globin?

A

Less beta globin to bind to
- less/absent HbA (alpha2beta2)
- increased HbA2 (alpha2delta2)
- increased HbF (alpha2gamma2)
- increased alpha4 (self-associate) -> unstable -> precipitate -> hemolysis

89
Q

Functions of Fe

A

Electron carrier -> Fe2+/Fe3+ interconversion

Carrier of molecular O2 in heme

90
Q

Where can you find Fe?

A

Heme (majority) and non-heme proteins

91
Q

Why is free Fe toxic?

A

It produces reactive O2 species

92
Q

Describe the flow/distribution of Fe in the body

A

Diet -> plasma -> loss

Plasma Fe -> used in erythropoiesis-> in RBC -> breakdown of RBC release Fe

Plasma Fe -> stored in liver (main storage)

Plasma Fe -> myoglobin

Plasma Fe -> non-heme proteins

93
Q

Is absorption of Fe better in heme or non-heme sources?

A

Heme sources

94
Q

Where is heme or Fe2+ absorbed?

A

Small intestine

95
Q

What forms of Fe can be absorbed in the small intestine?

A

Heme and Fe2+

96
Q

How is non-heme iron absorbed?

A

Bound to a ligand -> low pH stomach dissociates ligand -> Fe2+ absorbed

97
Q

What can promote conversion of Fe3+ to Fe2+?

A

Lower pH by using Vit C

98
Q

Flow of Fe during absorption

A

Fe3+ reduced to Fe2+ via ferric reductase -> Fe2+ enters small intestinal cell via divalent metal transporter 1 (DMT-1) -> Fe2+ transported across basement membrane via ferroportin -> converted to Fe3+ by hephaestin

99
Q

How is Fe transported?

A

As Fe3+ in complex with transferrin -> bind to transferrin receptor -> endocytosis -> acidification in endosome release Fe into cytoplasm -> receptor is recycled and transferrin released

100
Q

How is excess Fe stored?

A

Ferritin

Hemosiderin

101
Q

Which form of excess Fe is more readily accessible and mobilised?

A

Ferritin

102
Q

What does ferritin levels in plasma reflect?

A

Body’s iron stores

103
Q

Is ferritin levels always accurate?

A

No, it can be falsely elevated in chronic inflammatory states

104
Q

Can Fe be actively eliminated?

A

No

105
Q

How is Fe levels regulated?

A

Uptake of dietary Fe

Uptake of Fe/transferrin by liver

106
Q

What happens during low Fe state?

A

Increased uptake of dietary Fe by small intestine through increased expression of DMT-1 and ferroportin

Increased uptake of Fe/transferrin in liver through increased expression of transferrin receptor

107
Q

What happens during high Fe state?

A

Decreased uptake of dietary Fe by small intestine via decreased expression of DMT-1 and ferroportin with inhibition of ferroportin by hepcidin from liver

Decreased uptake of Fe/transferrin in liver via decreased expression of transferrin receptor and synthesis of hepcidin

Increased storage of Fe in liver by increased ferritin

108
Q

How can Fe be measured?

A

Plasma Fe -> amt of Fe usually bound to transferrin

Total iron binding capacity (TIBC) -> total transferrin amt

Unsaturated iron binding capacity (UIBC) -> transferrin not bound to Fe

Transferrin saturation -> % of transferrin occupied by Fe

Ferritin -> Fe body stores

109
Q

What causes Fe deficiency?

A

Decreased dietary intake

Increased need (pregnancy)

Increased loss (blood loss)

110
Q

Clinical indication of Fe deficiency?

A

Decreased plasma Fe

Decreased transferrin saturation

Decreased ferritin

110
Q

Complications of Fe deficiency

A

Anemia

111
Q

What can cause Fe excess?

A

Increased heme breakdown (due to genetics/toxins)

Increased Fe uptake (hemochromatosis)

112
Q

Clinical indications of Fe excess?

A

Increased plasma Fe

Increased transferrin saturation

Increased ferritin

113
Q

Complications of Fe excess?

A

Deposition skin

Organ damage (due to increased reactive O2 species)

114
Q

Acute Fe overload is lethal to…?

A

Children

115
Q

How do children get acute Fe overload?

A

Inadvertent ingestion of Fe supplements (cause they look like candy)

116
Q

Effects of acute Fe overload?

A

On gut:
- nausea/vomiting
- diarrhea
- GI bleeding

Systemic:
- increased reactive O2 species -> damage to heart

117
Q

How is Fe overload treated?

A

Chelators-> bind to Fe -> excreted in urine w/ reddish appearance (vin de rose)

Blood (9 decks)

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