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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
Heme breakdown (liver)
Bilirubin -> bilirubin diglucoronide (conjugated bilirubin) by UDP glucuronosyl transferase (UGT) - increase solubility of bilirubin - active transport into bile caniculi as bile; enter gut
26
Heme breakdown (gut)
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
27
Heme breakdown (blood)
Urobilinogen filtered through kidneys and excreted in urine - urobilinogen in urine oxidised to urobilin -> yellowish colouration of urine
28
Is unconjugated bilirubin soluble?
No
29
What is hyperbilirubinemia?
Total bilirubin (unconjugated + conjugated) > 1.2 mg/dL
30
How is hyperbilirubinemia detected?
Jaundice (>2.5-3 mg/dL)
31
Classification of hyperbilirubinemia and what it means?
Prehepatic -> excess bilirubin production Hepatic -> defective processing/excretion Obstructive -> block in excretion
32
Causes of prehepatic hyperbilirubinemia
Increased breakdown in RBC (hemolysis) -> increased bilirubin exceeding liver capacity
33
How does hemolysis cause prehepatic hyperbilirubinemia?
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
34
Characteristics of prehepatic hyperbilirubinemia
Increased unconjugated bilirubin Normal conjugated bilirubin Increased urobilinogen (in urine) - detect hyperbilirubinemia
35
Conditions that can cause hemolysis
G6PD/PK deficiency, malaria
36
How does severe hemolysis present
Dark urine (kopi-o colour)
37
Why does severe hemolysis cause dark urine?
Severe hemolysis -> increased free hemoglobin -> excreted n urine (hemoglobinuria) -> dark urine
38
Causes of hepatic hyperbilirubinemia
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
39
Changes in indices caused by disrupted reabsorption of urobilinogen
Increased urinary urobilinogen - due to increased levels of circulating urobilinogen filtered thru kidneys
40
Changes in indices caused by defective transport of conjugated bilirubin
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
41
Changes in indices caused by defective conjugation of bilirubin
Increased unconjugated bilirubin Decreased conjugated bilirubin Decreased urobilinogen - decreased stercobilin -> pale stools (severe)
42
Causes of defects in bilirubin conjugation
Genetic -> disrupt fn of UDP glucuronosyltransferase - Gilbert's syndrome (benign) (autosomal recessive) - Crigler-Najjar (possibly severe) Hormonal/drugs - thyroxine - estradiol contraceptive Physiological - neonatal immaturity
43
Causes of defective bilirubin excretion
Genetic -> defective transporter - Dubin-Johnson syndrome (rare) - Rotor syndrome (rare)
44
What does Dubin-Johnson syndrome cause?
Mutation in MRP2 transporter for excretion of conjugated bilirubin
45
Trait of Dubin-Johnson syndrome
Black liver
46
What is Rotor syndrome?
Mutation in SLCO I B I/B3 transporter
47
What causes jaundice due to mixed defects?
Hepatocyte dysfunction caused by infection, toxicity or autoimmune
48
Pathophysiology of early dysfunction
Defect in reabsorption Decreased excretion of conjugated bilirubin
49
Clinical findings during early dysfunction
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
(Pathophysio) What predominates when hepatocellular dysfunction worsens?
Defect in excretion of conjugated bilirubin
51
Clinical findings of progressive hepatocellular dysfunction
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
What causes obstructive jaundice?
Obstruction to bile duct from different etiologies
53
Classification of obstructive jaundice
Acquired Congenital
54
Examples of acquired obstructive jaundice
Bile duct stones Carcinoma Infection
55
Examples of congenital obstructive jaundice
Cysts Atresia
56
Clinical findings of obstructive jaundice
Increased conjugated bilirubin -> dark urine Conjugated bilirubin in urine Decreased urobilinogen Decreased stercobilin -> pale stools Increased unconjugated bilirubin (late)
57
What to suspect in excess free hemoglobin and the biochemical parameter changes?
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
Biochemical parameter changes during liver damage
Increased AST Increased ALT
59
Biochemical parameter changes during liver dysfunction
Decreased albumin Increased PT/PTT
60
Biochemical parameter changes during liver obstruction
Increased ALP Increased GGT
61
Causes of neonatal jaundice
Increased RBC lysis Decreased bilirubin conjugation (both result in increased unconjugated bilirubin -> can't be excreted)
62
Risk of high levels of unconjugated bilirubin to neonates
Cross immature BBB -> neurological damage (kernicterus)
63
Risk factors of neonatal jaundice
Blood group incompatibility G6PD deficiency Prematurity (BBB not fully formed/ liver can't conjugate bilirubin) Low albumin
64
Which babies have higher risk of hyperbilirubinemia?
Chinese (Gilbert's syndrome)
65
What is Gilbert's syndrome?
Mutation in UDP glucuronosyl-transferase (UGT)
66
Treatment for neonatal jaundice and their effects
Mild: blue-light phototherapy -> increase excretion of bilirubin Severe: exchange transfusion -> rapidly decrease bilirubin
67
How does blue-light phototherapy work?
Converts insoluble bilirubin to more soluble isomer (rotation ard double bonds)
68
What happens to heme?
Most used to make hemoglobin
69
What is hemoglobin?
Tetrameric protein made from 2 alpha and 2 beta subunits, each subunit contains heme grp for carrying O2
70
2 states of hemoglobin
Deoxy Hb - tissue - low O2 - high CO2 Oxy Hb - lung - high O2 - low CO2
71
Conditions for conversion of deoxy-Hb to oxy-Hb
High O2 Low H+
72
Conditions for conversion of oxy-Hb to deoxy-Hb
Low O2 High H+ Stimulated allosterically by 2,3-BPG
73
What type of globins is hemoglobin synthesised from?
Alpha type - zeta and alpha Beta type - epsilon, gamma, beta and delta
74
Predominant forms of hemoglobin during development and their subunits
Initial: Hb gower (zeta2epsilon2) Next: HbF (alpha2gamma2) Birth: HbA (alpha2beta2)
75
Predominant forms of hemoglobin in adults
HbA (alpha2beta2) - 90% HbA2 (alpha2delta2) HbF (alpha2gamma2)
76
Organisation of alpha and beta type globins
Organised in gene clusters on diff chromosomes -> 2 copies of alpha globin (chromosome 16) and 1 copy of beta globin (chromosome 11)
77
What can go wrong in hemoglobin synthesis?
Thalassemia (genetic)
78
What is thalassemia?
Defect in synthesis of alpha or beta globin genes - defect in alpha genes -> alpha thalassemia - defect in beta genes -> beta thalassemia
79
What kind of genetic disorder is thalassemia?
Autosomal recessive
80
Is thalassemia common in SEA?
Yes
81
Presentation of thalassemia
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
How does alpha and beta thalassemia arise?
Mutation of alpha and beta globin gene respectively
83
How many copies of alpha globin gene does a person have?
4 copies (2 per chromosome)
84
How is the severity of alpha thalassemia determined?
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
What happens when there is less alpha globin?
Less alpha globin to combine with - less HbA (alpha2beta2) - more gamma4 (self-associate) - more beta4 (self-associate) -> unstable -> precipitate -> hemolysis
86
How many copies of beta globin gene does a person have?
2 copies per individual
87
How is the severity of beta thalassemia determined?
The number of defective copies of beta globin gene - 1 defective copy -> minor -> mild symptoms - 2 defective copy -> major -> severe symptoms
88
What happens when there is less beta globin?
Less beta globin to bind to - less/absent HbA (alpha2beta2) - increased HbA2 (alpha2delta2) - increased HbF (alpha2gamma2) - increased alpha4 (self-associate) -> unstable -> precipitate -> hemolysis
89
Functions of Fe
Electron carrier -> Fe2+/Fe3+ interconversion Carrier of molecular O2 in heme
90
Where can you find Fe?
Heme (majority) and non-heme proteins
91
Why is free Fe toxic?
It produces reactive O2 species
92
Describe the flow/distribution of Fe in the body
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
Is absorption of Fe better in heme or non-heme sources?
Heme sources
94
Where is heme or Fe2+ absorbed?
Small intestine
95
What forms of Fe can be absorbed in the small intestine?
Heme and Fe2+
96
How is non-heme iron absorbed?
Bound to a ligand -> low pH stomach dissociates ligand -> Fe2+ absorbed
97
What can promote conversion of Fe3+ to Fe2+?
Lower pH by using Vit C
98
Flow of Fe during absorption
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
How is Fe transported?
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
How is excess Fe stored?
Ferritin Hemosiderin
101
Which form of excess Fe is more readily accessible and mobilised?
Ferritin
102
What does ferritin levels in plasma reflect?
Body's iron stores
103
Is ferritin levels always accurate?
No, it can be falsely elevated in chronic inflammatory states
104
Can Fe be actively eliminated?
No
105
How is Fe levels regulated?
Uptake of dietary Fe Uptake of Fe/transferrin by liver
106
What happens during low Fe state?
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
What happens during high Fe state?
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
How can Fe be measured?
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
What causes Fe deficiency?
Decreased dietary intake Increased need (pregnancy) Increased loss (blood loss)
110
Clinical indication of Fe deficiency?
Decreased plasma Fe Decreased transferrin saturation Decreased ferritin
110
Complications of Fe deficiency
Anemia
111
What can cause Fe excess?
Increased heme breakdown (due to genetics/toxins) Increased Fe uptake (hemochromatosis)
112
Clinical indications of Fe excess?
Increased plasma Fe Increased transferrin saturation Increased ferritin
113
Complications of Fe excess?
Deposition skin Organ damage (due to increased reactive O2 species)
114
Acute Fe overload is lethal to...?
Children
115
How do children get acute Fe overload?
Inadvertent ingestion of Fe supplements (cause they look like candy)
116
Effects of acute Fe overload?
On gut: - nausea/vomiting - diarrhea - GI bleeding Systemic: - increased reactive O2 species -> damage to heart
117
How is Fe overload treated?
Chelators-> bind to Fe -> excreted in urine w/ reddish appearance (vin de rose)

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