Haem metabolism for Medical students

1. HaemMetabolism & Disorders
Satya Bhushan Sharma
Assistant Professor

2. Haem Biosynthesis• Kuster established str. – 1912
• Linus Pauling – Abnormal Hb’s -1945
• Perutz – 3D Str. Of Hb. N.P. 1962
• Haem is derivative of ‘PORPHYRINS’.
Porphyrins are cyclic compounds formed by fusion
of 4 Pyrrole rings linked by methenyl (=CH-)
bridges.
• Haem is FERROPROTOPHYRIN
2SBS

3. PYRROLE RING
SBS 3

4. Porphyrins
SBS
I
II
III
IV
α …….∂ ARE METHENYL BRIDGES
4SBS

5. Porphyrins
• Substituents at 1,2,3,………8 are
Acetyl group (A) - CH2 - COOH
 Propionyl Group (P) -CH2 –CH2 – COOH
 Methyl Group (M) -CH3
 Vinyl Group (V) -CH2 = CH2
5SBS

6. Porphyrins
• Depending upon Substituent positions Porphyrins
are
•Sr.No
.
PORPHYRINS 1 2 3 4 5 6 7 8
1. UROPORPHYRIN I A P A P A P A P
2. UROPORPHYRIN III A P A P A P P A
3. COPROPORPHYRIN I M P M P M P M P
4. COPROPORPHYRIN III M P M P M P P M
5. PROTOPORPHYRIN III M V M V M P P M
6SBS

7. HAEM BIOSYNTHESISThe basic steps are
1. Synthesis of 4 Pyrrole rings
E1  ALA synthase & E2 ALA dehydratase
2. Joining of Pyrrole rings to form linear Tetrapyrrole
E3  PBG deaminase or UPG I synthase
3. Cyclization of linear Tetrapyrrole (UPG)
E4  UPG I or III co-synthase
4. Modifications of the side chains.
E5  UPG decarboxylase (Iron salts inhibits)
E6  CPG oxidase (does not act on CPG I)
5. Modifications of the linkages between Pyrroles
E7  PPG oxidase
6. Addition of Iron at the Center of Tetrapyrrole
E8  Ferrochelatase
SBS 7

8. HAEM BIOSYNTHESIS
Synthesized in almost all tissues by
NORMOBLASTS.
Pathway is partially Cytoplasmic and partially
Mitochondrial.
1. Aminolevulinic Acid Synthesis :
Catalyzed by ALA SYNTHASE a PLP dependant
enzyme present in Mitochondria.
 Alfa amino beta keto adipic acid is formed as an
intermediate.
 This step is RATE LIMITING.
8SBS

9. -
9SBS
Inhibited by Glucose
Intravenous Glucose is used to treat
/ relieve the Acute symptoms of
Acute Intermittent Porphyria

10. 2. PORPHOBILINOGEN (PBG) Synthesis
 Reaction takes place in cytoplasm.
 ALA Dehydratase/ PBG Synthase catalyze the Rxn.
2 2
10SBS

11. 3. Hydroxymethylbilane (HMB) Synthesis
SBS 11
E3
E3 – UPG I synthase / PBG deaminase
2

12. 4. UROPORPHYRINOGEN SYNTHESIS
• The Porphyrin ring is formed by condensation of 4 molecules
of Porphobilinogen (PBG).
• Porphobilinogen Deaminase catalyzes successive PBG
condensations, initiated in each case by elimination of the
amino group.
• Dipyrromethane group present in PBG Deaminase
catalyzes the formation of linear hexapyrrole .
• UPG-I Synthase & UPG-III cosynthase removes
Dipyrromethane.
• Macrocyclic UPG I & III is synthesized.
• UPG I  Uroporphyrin I & Excreted thru URINE.
 Uroporphyrinogen III is the precursor for synthesis of
Vitamin B12.
12SBS

13. 13SBS
E4
UPG I / III Cosynthase
HMB

14. SBS 14
E1 inhibited
by GLUCOSE

15. 5. COPROPHYRINOGEN III SYNTHESIS
UPG-decarboxylase removes carbonyl carbon as
CO2.
 Acetate group is decarboxylated to Methyl group.
15SBS

16. 6. PROTOPHYRINOGEN III SYNTHSIS
• Coproporphyrinogen Oxidase Oxidatively
decarboxylate Propionyl side chains of ring I & II
to Vinyl groups .
• CPG Oxidase is an NADPH dependent enzyme
• CPG Oxidase decarboxylate & Dehydrogenate
Propionyl side chains to Vinyl groups .
16SBS

17. 17SBS

18. 7.PROTOPORPHYRIN SYNTHESIS
PROTOPHYRINOGEN OXIDASE
dehydrogenate Methyl Bridges (-CH2- ) to
Methenyl Bridges (=CH-) Using Molecular Oxygen
(O2).
 Reaction takes place in MITOCHONDRIA.
 PP-IX is Synthesized.
 Two Water molecules are lost (-2H2O)
18SBS

19. .
PP IX
19SBS

20. 8. Haem Synthesis
Ferrocheletase a homodimeric enzyme
containing 2 iron-sulfur clusters Coordinately
link Fe++ to Protoporphyrin IX .
• Iron attaches to 4 Nitrogens of Pyrrole ring.
• 5th Coordination is satisfied by His of Globin.
20SBS

21. STRUCTURE OF HAEM
21SBS

22. SUMMARY
1. 8 molecules of Succinyl CoA & Glycine are required.
2. 8 Enzymes participates in the cascade
3. E1,6,7,8 are mitochondrial (rest Cytosolic)
4. E1 is rate limiting ( repressed by Haem & Glucose
and Induced by barbiturates & alcohol).
5. E2 & E8 are sulphahydryl enzymes
( inhibited by inorganic lead)
6. Humans can synthesize type III porphyrins only.
7. Porphyrinogens are auto-oxidized in light to
corresponding porphyrins (PPG oxidase can catalyse
conversion of PPG to porphyrins).
8.PPGs are colourless while porphyrins are coloured
SBS 22

23. SUMMARY
Enzyme deficiencies & Porphyrias
1. X-linked Sidroblastic Anaemia (E1-ALA synthase)
2. ALA dehydratase deficiency (E2-ALA dehydratase)
3. Acute Intermittent Porphyria (E3-PBG deaminase)
4. Congenital Erythropoietic porphyria
(E4- UPG I / III cosynthase)
5. Porphyria Cutanea Tarda (E5-UPG decarboxylase)
6. Hereditary Coproporphyria (E6-CPG oxidase)
7. Variegate Porphyria (E7-PPG oxidase)
8. Erythropoietic porphyria (E8- Ferrochelatase)
SBS 23

24. Erythropoietic Protoporhyria
24SBS
E1
E2
UPG III cosynthase
X-linked Sidroblastic Anaemia
Hereditary Coproporphyria

25. REGULATIONALA Synthase is inhibited by HAEM which act as
co-repressor.
 Hematin also inhibit ALA Synthase (Allosterically)
Non - Erythroid –Repressible (Ch. 3)- ALAS1
 Erythroid – Non Repressible (Ch. X)- ALAS2
High cellular Glucose conc. repress HAEM synthesis
by activating Catabolite Repressor Protein.
 ALA dehydratase & Ferrochelatase are inhibited by
LEAD.(Cause of Acquired Porphyria & anemia )
PLP Availability regulates HAEM Synthesis.
Isonicotinic Acid Hydrazed (ATT-INH) reduce PLP availability.
2/3 of HAEM  cyt.P450.
 Barbiturates require cyt.P450 mechanism for their
Metabolism
25SBS

26. HAEM CATABOLISM
Within cells of the RE system(LIVER,SPLEEN & BONE MARROW) Haem
is degraded to Bilirubin in a two-step process .
A. The Porphyrin ring is opened and the iron atom is
removed by the action of
Haem oxygenase (Induced by HAEM) produce the
green-colored intermediate Biliverdin.
 Fe++ is converted to Fe+++ & taken up by
TRANSFERRIN
B. Subsequent reduction converts Biliverdin to
Bilirubin, which has a Red orange color.
26SBS

27. .
The Globin is recycled or converted into amino acids,
which in turn are recycled or catabolized as required.
Haem is oxidized, with the Haem porphyrin ring being
opened by the endoplasmic reticulum enzyme,
Haem oxygenase (induced by HAEM).
The oxidation occurs on a specific carbon producing
Equimolar amounts of the Biliverdin, Iron , and
Carbon monoxide (CO).
This is the only reaction in the body that is
known to produce CO.
Most of the CO is excreted through the lungs.
The CO content of exhaled air is a direct measure of
the activity of Haem oxygenase in an individual. 27SBS

28. .
In the first reaction, a bridging methylene group is
cleaved by Haem oxygenase to form Linear
Biliverdin from Cyclic HAEM molecule.
Fe2+ is released from the ring in this process
28SBS
P

29. .
• 1
Fe++  Fe+++
(TRANSFERRIN)
AMINO ACID POOL  GLOBIN CHAIN
HAEM OXYGENASENADPH & cyt. C
Haem oxygenase is induced by
HAEM
III IIIVI
29SBS

30. In the next reaction, a second bridging methylene
(between rings III and IV) is reduced by NADPH
dependent Biliverdin reductase, producing Bilirubin.
IVI III II
30SBS

31. TRANSPORT of BILIRUBINBilirubin produced in RE cells is Lipophilic in nature
 Lipophilic Albumin – Bilirubin complex is transported
in plasma
 1 molecule of Albumin can bind to 2 molecules of
Bilirubin.
 Plasma can Transport up to 25mg/dl of Bilirubin.
 Albumin – Bilirubin complex is loosely bound
 Binding sites for Bilirubin on albumin can be occupied
by:
 Aspirin ,penicillin & sulfa drugs.
These Drugs should not be administered to New-Born
babies to avoid Kernicterus
31SBS

32. TRANSPORT of BILIRUBIN At sinusoidal surface of Liver, Albumin – Bilirubin is
dissociated.
Bilirubin is taken by the liver , by Active - carrier
mediated process
 Z-protein & Ligandin binds to Bilirubin in liver.
 Conjugation with Glucuronides in Hepatic –
microsomes make Bilirubin Water – soluble
 C-1 of Glucuronic Acid combines with >CO gp. of
Propionic acid side chain of Bilirubin.
80% of Bilirubin is in diglucuronide form
 Primaquine ,Novobiocin, Chloramphenicol
Androgens & Pregnanediol interfere in conjugation
32SBS

33. TRANSPORT of BILIRUBIN
33SBS

34. .
< 10%
34SBS

35. .
Bilirubin Mono & Di Glucuronides are produced in Hepatic
Microsomes by the action of UDP- Glucuronyl Transferase.
Bilirubin Mono Glucuronides can also be converted to
Bilirubin Di Glucuronides by the action of Bilirubin dismutase.
(Bases of Crigler-Najjar syndrome I & II)
I IV III II
35SBS

36. .
Conjugated (water soluble) Bilirubin is
excreated in to bile against conc. gradient
 Rate limiting step in HAEM catabolism.
 Induced by Phenobarbitone.
Excretion of Conj. Bilirubin in Bile is mediated
by an ATP binding cassette protein
“Multispecific organic anion transporter”
(MOAT) present in PM of Biliary Canaliculi
 MOAT is deficient in Dubin- Johnson
 Intestinal Bacteria deconjugate it.
 Bilirubin is reduced to UROBILINOGEN.
 20% of UBG is reabsorbed & returned to
Liver by PORTAL BLOOD (Entero- hepatic
circulation ) 36SBS

37. Further reduction at the keto group of terminal side
chains converts Bilirubin to UROBILINOGEN
UROBILINOGEN
I IV III II
37SBS

38. .
Urobilinogens is a collective term for a group
of 3 Tetrapyrroles;
– Urobilinogen
Reduction at venyl side chain
– Mesobilinogen
Reduction at venyl side chain
– Stercobilinogen (250-300mg/day thru feces)
Up to 20 % of Urobilinogen produced daily is
reabsorbed from the intestine & enters the
entero-hepatic circulation
38SBS

39. 39SBS

40. .
• Most of the reabsorbed Urobilinogen is taken up by the liver
& is re-excreted in the bile.
• A small fraction (2 % - 5 %) enters the general circulation &
appears in the urine.
• In the lower intestinal tract, the 3 Urobilinogens
spontaneously oxidize to produce the corresponding
bile pigments ;
– Urobilin 4mg/day thru Urine
–Mesobilin &
–Stercobilin
which are ORANGE-BROWN in color and are the
major pigments of stool.
40SBS

41. Serum Bilirubin Levels
Total Bilirubin - 0.2-0.8 mg/dl
 Conjugated Bilirubin - 0-0.2 mg/dl
 Bilirubin levels > 1mg/dl - Hyperbilirubnemia
 Bilirubin Levels 1-2 mg/dl –Latent Jaundice
 More than 2 or 2.5mg/dl causes Yellowish
discoloration of
 Sclera , Conjunctiva , Skin & Mucous Membrane
 Icterus is the Greek term for Jaundice
41SBS

42. Congenital Hyperbilirubinemias
Due to abnormal Uptake , Conjugation or
excretion of Bilirubin due to Inherited Defects
 All are autosomal recessive except Type II CN
1. Crigler – Najjar Syndrome I & II
2. Gilbert- Meulengracht’s Syndrome
3. Dubin – Jonnson Syndrome
4. Rotor Syndrome
5. Lucey – Driscoll Syndrome
42SBS

43. Crigler – Najjar Syndrome I
A super rare, autosomal recessive disorder in which
patients have NO UDP- Glucuronyl Transferase
( UGT1A1) activity.
 The bile is colorless, with only trace amounts of
unconjugated Bilirubin
 Jaundice appears within 24 hrs of Life
 Serum Bilirubin levels ↑ beyond 20mg/dl
 Kernicterus occurs
 No response to Phenobarbitone
Exchange Transfusion in the immediate neonatal
period
12 hours/day phototherapy 43SBS

44. Crigler – Najjar Syndrome II
UDP- Glucuronyl Transferase (UGT1A1 ) is present
at reduced but detectable levels (<10% of normal).
 Kernicterus is rare in type II.
 Monoglucuronides are present
 Treatment with Phenobarbitone is effective &
↓ Bilirubin by 25%.
 Bilirubin Monoglucuronides dismutase converts
monoconjugates to Diconjugates.
 The condition is named for J. F. Crigler, an
American pediatrician and V. A. Najjar a Lebanese-
American pediatrician 44SBS

45. Gilbert- Meulengracht’s Syndrome
Most common Hereditary cause of Hyperbilirubinemia
( 10% in Caucasian people)
 UDP- Glucuronyl Transferase (UGT1A6 ) is present at reduced
but detectable levels (< 30% of normal).
Gilbert's syndrome is more often a consequence
of heterozygote mis -sense mutation.
GS can be classified as a minor inborn error of metabolism.
Levels of Bilirubin in GS patients are reported to be 1.2 to
5.3 mg/dl (<3mg/dl)
 Respond to Phenobarbitone
In GS, ALT and AST, as well as Albumin are within normal
ranges
Several analysis have found a ↓↓ risk of coronary artery
disease (CAD) in individuals with GS 45SBS

46. Dubin – Jonnson Syndrome
Conjugated Hyperbilirubinemia
 defect in secretion of Bilirubin glucuronides across
the Biliary canalicular membrane.
 ATP dependent “Multispecific organic anion
transporter” (MOAT) is deficient
 Conjugated Bilirubin get deposited in Liver.
A darkly pigmented liver is due to polymerized
epinephrine metabolites causing “Black Liver
Jaundice”
 Phenylalanine , Tyrosine & Tryptophan like organic
anions are accumulated as MOAT is deficient.
ALT , AST and GGT as well as Albumin are within
normal ranges
46SBS

47. Rotor Syndrome
Rare Autosomal Recessive conjugated
Hyperbilirubinemia.
Bilirubin Excretion is defective.
 Organic anion transporting polypeptide 1B1
(OATP1B1) and 1B3 (OATP1B3) are defective,
 Bilirubin is not taken up by Liver
 Hepatocytes are not pigmented
 Non-itchy Jaundice
 Most patients are asymptomatic (other than
some degree of jaundice).
47SBS

48. Lucey – Driscoll Syndrome
Transient familial hyperbilirubinemia
 A rare metabolic disorder leading to very high
levels of Bilirubin in a newborn's blood.
Babies with LDS are born with severe
jaundice ,yellow eyes and lethargy.
 Kernicterus occurs
 Mutation in the UDP- Glucuronyl Transferase
(UGT1A1 ) gene cause ↑ levels of Inhibition of
conjugation by Pregnanediol .
 Exchange Transfusion in the immediate neonatal
period
12 hours/day phototherapy
48SBS

49. Uses of Porphyrins
• Because of the unique chemistry of porphyrins, they
are able to serve in several ways:
– As a metal binder (ligands)
– As a solar cell (convert light or chemical energy)
As an oxygen transport medium (hemoglobin)
– As an electron transfer medium (conducting polymers)
– Gene regulation
– Drug metabolism
– Iron metabolism
– Hormone synthesis
49SBS

50. Photodynamic Therapy
• Porphyrins are commonly used as light-
absorbing compounds which are “switched
on” by photons of light and then react with
cells in a desired way.
Photodynamic therapy (PDT) -fiber optic
surgery
A photosensitive drug absorbed by cancer cells
can be activated by a laser beam guided
through optical fibers to selectively destroy a
tumor.
These drugs are also used to treat other
conditions, such as acne. 50SBS

51. Porphyrias
• Porphyrias are a set of diseases that result from
enzyme deficiencies in the heme biosynthesis
pathway.
• Heme is mostly used for its incorporation into
haemoglobin and role in red blood cells, but is also
needed for Cytochrome P450 function.
• Each disease is associated with a deficiency in one
of the eight enzymes in the pathway.
• They fall under two categories based on their
clinical symptoms:
Acute hepatic and Erythropoietic Porphyrias.51SBS

52. g
SBS 52
Erythropoietic Protoporhyria

53. Disease Mechanism
 Generally, the disease mechanism for Porphyrias
is that their respective enzymatic deficiencies lead
to the accumulation of porphyrins and porphyrin
precursors that ultimately produce free radicals.
For acute hepatic Porphyrias, ∂- aminolaevulinic
acid (ALA) and Porphobilinogen (PBG) accumulate
and produce free radicals via auto- oxidation.
53SBS

54. Disease Mechanism
Deficiency of an enzyme in cascade blocks the distal
part .
Haem synthesis is reduced
ALA synthase is de repressed
Proximal metabolites get accumulated.
Alcohol & barbiturates ingestion can trigger the
symptoms.
 Pre-cyclization defects have predominantly
Neurovisceral & Neuropsychiatric manifestations.
 ALA & PBG are increased in blood & urine
SBS 54

55. Disease Mechanism
Post cyclization defects results in enhanced
synthesis of corresponding Porphyrinogens.
 They get converted to respective Porphyrins
 Porphyrins get deposited in skin & get excited on
UV exposure.
 Porphyrins get excreted thru Urine & Faeces.
 Management :
1. Avoid Alcohol & Barbiturates
2. Administer IV Dextrose or haematin
3. Administer β-carotene to supress skin reactions.
SBS 55

56. Disease Mechanism
 For Erythropoietic Porphyrias, Uroporphyrins (UP)
Coproporphyrins (CP) and protoporphyrins (PP)
accumulate and produce free radicals via the
absorption of visible light.
The generated free radicals participate in oxidative
stress reactions, such as lipid oxidation and protein
cross linking, that lead to membrane and
mitochondrial damage, ultimately promoting cell
death.
Loss of negative feedback of Haem leads to further
accumulation of porphyrins.
SBS 56

57. Disease Mechanism
 Porphyrins build up in the body and are excreted
in the urine and stool in excessive amounts. When
present in very high levels, they cause the urine to
have a spectacular port wine color.
SBS 57

58. Disease Mechanism
King George III - Mad King George
had acute bouts of abdominal pain and
mental confusion
- may have been Porphyria sufferer
- complicated by all the drugs his doctors gave him
Vampires and werewolves ?
- some have put forth that Porphyrias misinterpreted
 in Middle Ages
- consider photosensitivity, red blood (even teeth)
- hypertrichosis (PCT )
SBS 58

59. Signs & Symptoms
• Symptoms of Cutaneous Forms
Occur most commonly with exposure to sunlight
Mainly skin symptoms that occur
Due to excess porphyrins that accumulate in
surface of skin
Symptoms:
Fluid filled blisters
Changes in pigmentation ( castle’s necklace)
Breakdown (necrosis) of the skin when exposed to sunlight
Overall skin can become scarred, brown, blotchy and
fragile 59SBS

60. Symptoms of Acute Forms
 Originate mainly in nervous system
 Symptoms last around 1-2 weeks
 Possible mechanisms include damage by free radicals, direct
neurotoxicity of ALA, and the deficiency in nervous tissue
Symptoms:
 Severe abdominal pain
 Muscle weakness and pain, tingling, or numbness and possibly
paralysis
 Pain in arms, legs, back
 Constipation
 Vomiting , Diarrhea
 Insomnia , Seizures and Confusion
 Anxiety and paranoia
 Fever
60SBS

61. Treatment
Cutaneous Forms
• Avoiding sunlight
• Attention to skin care
• Beta-carotene supplements
 Function to neutralize the effects of reactive
protoporphyrins
61SBS

62. Treatment for Acute Forms
Several treatments can be used to control neurological
symptoms and defective heme production:
 Carbohydrate such as glucose
To help limit the synthesis of Porphyrins
 Phlebotomy (removal of blood)
To reduce excessive iron stores which improves heme synthesis
 Sedatives to help with anxiety
 Pain medications such as opiates
 Hematin given intravenously
Hematin are heme-like substances that inhibit ALA synthase
and the accumulation of toxic precursors
62SBS

63. X-linked Sidroblastic Anaemia
ALA synthase is deficient
Ringed sideroblasts rather than healthy red
blood cells (erythrocytes) are produced.
 iron can not be incorporated to haem.
 Acquired Sidroblastic Anaemia
1. Lead toxicity
2. Ethanol , INH, chloramphenicol induced.
3. Copper & PLP deficiency
SBS 63

64. ALA dehydratase deficiency
porphyria(DOSS porphyria)
ALA dehydratase
• Autosomal recessive
• Very rare
• Symptoms: Abdominal pain, neuropathy
δ- ALA Porphobilinogen
64SBS

65. Acute intermittent porphyria (AIP)
 2nd most common form of porphyria
 Caused by deficiency of PBG deaminase or
ALA dehydratase
 Metabolite Porphobilinogen(PBG) accumulates in
cytoplasm
Symptoms:
Localized abdominal pain, Urinary symptoms
Peripheral neuropathy raised concentration of urinary
porphyrins
Treatment
Hematin, Heme arginate
Do not cure but reduces symptoms
Inhibit ALA synthase which occurs at the beginning of HAEM
biosynthesis
65SBS

66. .
Congenital Erythropoietic Porphyria
• Deficiency of Uroporphyrinogen III co-synthase
• Rare autosomal recessive (1 in 1,000,000)
Severe photosensitivity & develop skin lesions.
 Porphyrins accumulate under the skin, in
normoblasts & RBC’s.
 Erythrodontia & Pink colored Skin
 UPG III is not synthesized , δ-ALA Synthase
activity ↑ thus porphyrins of I series( UP I or CP I)
increases in Blood
 PBG & δ-ALA are present in Urine.
 Port wine or Red colored Urine
66SBS

67. .
Hereditary coproporphyria
• Deficiency of Coproporphyrinogen III Oxidase
• Autosomal dominant
• No cure exists
Porphyria Cutanea Tarda
UPG decrboxylase is partially deficient
 Uroporphyrins are deposited under the skin.
 Photosensitivity is the Prominent symptom.
 Concentration of UP’s & CP’s ↑ in Urine
specially their Zinc complexes.
67SBS

68. Porphyria Cutanea Tarda (PCT)
Most common porphyria
Classified as such when Uroporphyrinogen decarboxylase
activity <20%
Hepatic disorder
Inherited or obtained through Hepatitis C, drugs, alcohol,
poisons
Treatment: discourage risk factors and treat symptoms;
can draw blood to reduce iron in the liver until the
serum ferritin reaches normal iron levels.
Chloroquine or hydroxychloroquine can move excess
porphyrins from the liver and promote excretion.
Can be used when drawing blood is not recommended.
Avoid causes of PCT
68SBS

69. Variegate Porphyria
 Protoporphyrinogen IX- Oxidase is Deficient
Autosomal dominant .
 Relative Heme deficiency leads to activation of
δ-ALA Synthase activity thus porphyrins of I
series increases in Blood.
 the precursors overproduction leads to D.O.
 clinical presentation is Mixed.
 Abdominal , Neurological & Cutaneous
symptoms are there.
 Acute abdominal pain , nausea ,Vomiting , CNS
symptoms & cutaneous involvement. 69SBS

70. Erythropoietic Protoporhyria
Ferrochelatase is deficient
 Heme is not synthesized
 Autosomal dominant
Photosensitivity- can be managed by limiting
exposure
 Anaemia
 Erythrodontia & Pink colored skin
 CASTLE’S NECKLACE
70SBS

71. Acquired Porphyrias
 Hexochlorobenzene used as a fungicide in Turkey in 1950s
- thousands of children ate bread from treated wheat
- They acquired Porphyria Cutanea Tarda
due to inhibition of uroporphyrinogen
decarboxylase
- due to hypertrichosis – they are
referred to locally as the
“monkey children”

72. Acquired Porphyrias
Lead poisoning
-inhibition of ferrochelatase, ALA dehydratase
- displaces Zn2+ at enzyme active site
Children
- developmental defects
- drop in IQ
- hyperactivity
- insomnia
- many other health problems
Adults
- severe abdominal pain
- mental confusion
- many other symptoms

73. .
Porphyria is caused by a deficiency in any of the 8 enzymes
of heme synthesis.
Which Leads to the build up of heme precursors
Divided into two categories based on clinical symptoms:
acute hepatic and Erythropoeitic
Enzymatic deficiencies are inherited, but symptoms may not
appear unless induced by environmental agents.
Main symptoms associated:
 porphyrin accumulation in various locations,
photosensitivity, pain, numbness, vomiting, and seizures.
Treatment:
Reduce symptoms with related drugs
Encourage excretion or removal of heme precursors 73SBS

74. .
74SBS

75. THANK YOU
75SBS