briefly about heme synthesis and porphyrias ,classification,diagnosis,management, and prevention

1. Heme synthesis and porphyrias

2. • Hemoglobin
• Myoglobin
• Cytochromes
• Peroxidase
• Catalase
• Tryptophan pyrrolase
• Nitric oxide synthase.
Heme is present in:

3. Hemoglobin contain how many Heme groups?
Hemoglobin contain four Heme groups

4. Each Heme contain how many iron atoms?
Each Heme holds one iron atom, each iron atom
holds one molecule of oxygen

5. Each hemoglobin carries how many oxygen
molecules?
Four oxygen molecules

6. How much hemoglobin is in each red blood
cell?
• 250 million molecules of hemoglobin per cell.
• Each red blood cell carries one billion
molecules of oxygen.

7. Organs mainly involved in Heme synthesis ?
variable
constant

8. Which part of the cell does the Heme synthesis
take place?

9. cytosolmitochondria

10. Heme
Bile pigments + iron
Heme
degradationHeme synthesis

11. What are porphyrias ?
• Porphyria refers to a growing collection of
disorders in which there are abnormalities in the
enzymes involved in Heme synthesis.
• Although porphyrias are not very prevalent,
physicians must be aware of them.

12. How is the structure of porphyrin ?
• Porphyrins are cyclic compounds formed by
the linkage of four pyrrole rings through
methyne (=HC —) bridges
• A characteristic property of porphyrins is the
formation of complexes with metal ions
bound to the nitrogen atom of the pyrrole
rings

13. Structure of Heme

14. What causes porphyrias?
• There are at least eight steps in the
production of Heme, and at least eight
different types of porphyria can result when
an enzyme malfunctions and levels of
intermediate substances rise to beyond what
the body is accustomed to.

15. Heme synthesis
step by step

17. Step-1 (mitochondria)
Succinyl-CoA Glycine
From citric acid cycle Non essential amino acid
( Pyridoxal phosphate activates )
α-amino-β-ketoadipic acid
condensation reaction
ALA
synthase
CoA-SH

18. Step-2 (mitochondria)
α-amino-β-ketoadipic acid
δ-aminolevulinate (ALA)
decarboxylation reaction ALA synthase
(rate controlling enzyme -
porphyrin biosynthesis –
liver)

19. Step-3 (cytosol)
( 2molecules )
δ-aminolevulinate (ALA)
ALA dehydratase
(1) porphobilinogen (PBG)
zinc-containing enzyme and is
sensitive to inhibition by lead.
2H20
First precursor of pyrrole

20. (4molecules)
porphobilinogen (PBG)
Step-4(cytosol)
Hydroxymethylbilane (HMB)
(linear tetrapyrrole)
uroporphyrinogen I
synthase
4NH3
condenses
PBG deaminase
HMB synthase
AIP

21. Step-5 (cytosol)
Hydroxymethylbilane (HMB)
uroporphyrinogen I
uroporphyrinogen III
(HMB cyclizes spontaneously)
uroporphyrinogen III
synthase
Forms under normal conditions
CEP

22. uroporphyrinogen I uroporphyrinogen III
coproporphyrinogen I coproporphyrinogen III
light6H
Uroporphyrin I
6H
light
Coproporphyrin I
Uroporphyrinogen
decarboxylase
6H
Uroporphyrin III
6H
Coproporphyrin III
light
light
Step-6 (mitochondria)
PCT

23. coproporphyrinogen III
Protoporphyrinogen III
Step-7 (mitochondria)
Coproporphyrinogen
oxidase
HCP

24. Protoporphyrinogen III
Protoporphyrin III
Protoporphyrinogen
oxidase
Step-8 (mitochondria)
Por.variegata

25. Step-9 (mitochondria)
Protoporphyrin IX
Ferrochetalase
Heme
H.protoporphyria
Heme synthase

27. Regulation of Heme Synthesis
• Heme inhibits the synthesis of ALA synthase
(repression mechanism)
• ALA synthase is also allosterically inhibited by
hematin.
• The compartmentalization of the enzymes,
makes the regulation easier.
• The steps catalyzed by ferrochelatase and ALA
dehydratase are inhibited by lead.

28. • Drugs like barbiturates induce heme synthesis.
Barbiturates require the heme containing
cytochrome P450 for their metabolism. Out of
the total heme synthesized, two thirds are used
for cytochrome P450 production.
• INH (Isonicotinic acid hydrazide) that decreases
the availability of pyridoxal phosphate may also
affect heme synthesis.
Regulation of Heme Synthesis

29. • High cellular concentration of glucose
prevents induction of ALA synthase. This is the
basis of administration of glucose to relieve
the acute attack of porphyrias.
• Regulation in the erythroid cells :
The enzyme ALA synthase does not appear to
control the heme synthesis in the erythroid
cells. Uroporphyrinogen synthase and
ferrochelatse mostly regulate heme formation
in these cells
Regulation of Heme Synthesis

30. Porphyrias classification
• This classification is based on the major site,
where the enzyme deficiency is manifested.
• The porphyrias are classified as
erythropoietic or hepatic, depending on
whether the enzyme deficiency occurs in the
erythropoietic cells of the bone marrow or
in the liver.
• Hepatic porphyrias can be further classified
as chronic or acute

31. • In general, individuals with an enzyme defect
prior to the synthesis of the tetrapyrroles
manifest abdominal and neuropsychiatric signs
• whereas those with enzyme defects leading to
the accumulation of tetrapyrrole intermediates
show photosensitivity
(that is, their skin itches and burns [pruritus]
when exposed to visible light).
Porphyrias classification

32. Porphyrias inheritance
All types of porphyrias
exhibit this pattern of
inheritance except
congenital erythropoietic
porphyrias

33. CEP- inheritance
Autosomal recessive
inheritance

34. (4molecules)
porphobilinogen (PBG)
Acute intermittent porphyria
Hydroxymethylbilane (HMB)
(linear tetrapyrrole)
Uroporphyrinogen
I synthase
condenses
This disorder occurs due to the deficiency of
the enzyme uroporphyrinogen I synthase.
 Characterized by increased excretion of
porphobilinogen and 6-aminolevulinate.
The urine gets darkened on exposure to air
due to the conversion of porphobilinogen to
porphobilin and porphyria.

35. Other characteristic features of AIP
• Usually expressed after puberty in humans
• The symptoms include abdominal pain, vomiting and
cardiovascular abnormalities
• The neuropsychiatric disturbances observed.
• The symptoms are more severe after administration of
drugs (e.g. barbiturates)
• These patients are not photosensitive since the
enzyme defect occurs prior to the formation of
uroporphyrinogen.

36. "madkingwholost America"
King George lll ruled England
during the period of American
revolution.
 He was a victim of this
disease AIP and possessed the
characteristic manifestations
and was considered mad.
The decisions taken by the
deranged King due to acute
intermittent porphyria had led
to a war followed by American
Independence.

37. Hydroxymethylbilane
uroporphyrinogen III
Congenital erythropoietic porphyria
uroporphyrinogen III
synthase
characteristic features
Rare congenital disorder
Autosomal recessive
Confined to erythropoietic
tissues.
The individuals excrete
uroporphyrinogen I and
coproporphyrinogen I which
oxidize respectively to uroporphyrin
I and coproporphyrin | (red
pigments).
 The patients are photosensitive
 Increased hemolysis

38. uroporphyrinogen I uroporphyrinogen III
coproporphyrinogen I coproporphyrinogen III
Uroporphyrinogen
decarboxylase
porphyria cutanea tarda
 This is also known as cutaneous hepatic porphyria
 The most common porphyria .
Usually associated with liver damage caused by alcohol
overconsumption or iron overload.
The partial deficiency of the enzyme uroporphyrinogen
decarboxylase appears to be responsible for the occurrence of
porphyria cutanea tarda.

39. The other characteristic features include:
• Increased excretion of uroporphyrins (l and lll)
and rarely porphobilinogen.
• Cutaneous photosensitivity is the most important
clinical manifestation of these Patients.
• Liver exhibits fluorescence due to high
concentration of accumulated porphyrins.
porphyria cutanea tarda

40. coproporphyrinogen III
Protoporphyrinogen III
Hereditary cutaenia tarda
Coproporphyrinogen
oxidase
Coproporphyrinogen lll and other intermediates (ALA and PBC)
excreted in urine and feces.
The victims of hereditary coproporphyria are photosensitive.
 They exhibit the clinical manifestations observed in the patients
of acute intermittent porphyria.
 Infusion of hematin is used to control this disorder.
 Hematin inhibits ALA synthase and thus reduces the
accumulation of various intermediates.

41. Protoporphyrinogen III
Protoporphyrin IX
Protoporphyrinogen
oxidase
Variegate porphyria
The enzyme protoporphyrinogen oxidase is defective in this
disorder.
Due to this blockade, protoporphyrin lX required for the ultimate
synthesis of Heme is not produced.
Almost all the intermediates (porphobilinogen, coproporphyrin,
uroporphyrin, protoporphyrin etc.) of Heme synthesis accumulate
in the body and are excreted in urine and feces.
The urine of these patients is coloured and they exhibit
photosensitivity.

42. protoporphyria
Protoporphyrin IX
Ferrochetalase
Heme
Heme synthase
This disorder, also known as erythropoietic protoporphyria
Deficiency of the enzyme ferrochelatase.
Protoporphyrin lX accumulates in the tissues and is
excreted into urine and feces.
Reticulocytes (young RBC) and skin biopsy exhibit red
flourescence

43. Acquired porphyrias (toxic)
• The porphyrias, though not inherited, may be acquired
due to the toxicity of several compounds.
• Exposure of the body to :
 Heavy metals (e.g. lead),
 Toxic compounds (e.g hexachlorobenzene)
 Drugs
(e.g. griseofulvin inhibits many enzymes in heme
synthesis)
These include:
 ALA dehydratase,
 Uroporphyrin I synthase
 ferrochetalase

44. • The best time to attempt diagnosis is when the
symptoms are active.
• Porphyria sufferers are affected by anything that
can alter the functioning of the deficient
enzymes.
• Disease can occur to different degrees. Some
people are affected so slightly that the diagnosis
is never considered.
• Herbs, drugs, alcohol and even hormones can
produce acute attacks by interfering with enzyme
function.
Diagnosis

45. • Lab tests are required to make a definitive
diagnosis of porphyria and to determine
which form of the disease you have.
• If your doctor suspects porphyria, he or she
may recommend these tests:
• Urine , blood and stool examination for
various porphyrins.
• Spectrophotometry Is Used to Test for
Porphyrins & Their Precursors
Coproporphyrins and uroporphyrins
Diagnosis

46. • Urine test:
If you have a form of acute porphyria, a urine test
may reveal elevated levels of two substances:
porphobilinogen and delta- aminolevulinic acids,
as well as other porphyrins.
• Blood test:
If you have a form of cutaneous porphyria, a blood
test may show an elevation in the level of porphyrins
in your blood plasma.
• Stool sample test:
Analysis of a stool sample may reveal elevated levels
of some porphyrins that may not be detected in urine
samples. This test may help your doctor determine
your specific type of porphyria.

47. • To demonstrate porphyrins, UV fluorescence is
the best technique.
• The presence of porphyrin precursor in urine is
detected by Ehrlich’s reagent.
• When urine is observed under ultraviolet light
porphyrins if present, will emit strong red
fluorescence.
• Spectrophotometry Is Used to Test for
Porphyrins & Their Precursors Coproporphyrins
and uroporphyrins.
• use of appropriate gene probes has made
possible the prenatal diagnosis of some of the
porphyrias.

48. • Treatment depends on the type of porphyria you have and is
directed at relieving symptoms.
• Acute porphyrias
• Treatment of symptoms and preventing complications.
Treatment may include:
 Stopping medications that may have triggered symptoms
 Medication to control pain, nausea and vomiting
 Prompt treatment of infections or other illness that may have
caused symptoms
 Intravenous sugar (glucose) or sugar taken by mouth, if able,
to maintain an adequate intake of carbohydrates
 Intravenous fluids to combat dehydration
 Injections of hemin, a medication that is a form of heme, to
limit the body's production of porphyrin
Porphyrias management

49. • Cutaneous porphyrias
• Treatment of cutaneous porphyrias focuses on
reducing exposure to sunlight and the amount of
porphyrins in your body to help eliminate your
symptoms. This may include:
• Drawing blood (phlebotomy): Drawing a certain
amount of blood from one of your veins.
• Medication: Drugs used to treat malaria —
hydroxychloroquine or, less often, chloroquine can
absorb excess porphyrins and help your body get rid
of them more quickly than usual. These medications
are generally used only in people who can't tolerate
a phlebotomy.

50. • Beta carotene: Long-term treatment of
cutaneous porphyrias may include daily doses
of prescription beta carotene. Beta carotene
may increase your skin's tolerance to sunlight.
• Reducing or eliminating triggers: Triggers, such
as certain medications or too much sunlight,
which activated the disease, should be reduced
or removed if possible .
• Vitamin D: Supplements may be recommended
to replace vitamin D deficiency caused by
avoidance of sunlight.

51. Life style and Home remedies
• If you have porphyria:
• Learn what could trigger symptoms:
Talk to your doctor about the type of porphyria you have
and become familiar with possible symptom triggers and
ways to avoid them.
• Inform your health care providers:
Tell all your health care providers that you have porphyria.
This is particularly important because sometimes
treatments, medications or surgery can trigger porphyria
symptoms.
• Wear a medical alert bracelet or necklace:
Have information about your condition inscribed on a
medical alert bracelet or necklace, and always wear it.

52. • Although there's no way to prevent porphyria.
• If you have the disease, these steps may help
prevent symptoms:
Avoid medications known to trigger acute attacks.
Ask your doctor for a list of safe and unsafe drugs.
Don't use alcohol or illegal drugs.
Avoid fasting and dieting that involves severe
calorie restriction.
Don't smoke.
Prevention

53. • Minimize sun exposure. When you're
outdoors, wear protective clothing and use a
broad-spectrum sunscreen with a high sun
protection factor (SPF).
• Treat infections and other illnesses promptly.
• Take steps to reduce emotional stress.
• Because porphyria is an inherited disorder,
your siblings and other family members may
want to consider genetic testing to determine
if they have the disease.
Prevention

54. Think porphyria

55. Thank you