Porphyrias and Errors In
Heme Metabolism
By:
Maria Moreno, Jin-Hee Park,
Seo Youn Kim and Newton Wong
September 23, 2014
PHM142 Fall 2014
Instructor: Dr. Jeffrey Henderson
Outline
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What is Heme?
Heme Synthesis
Porphyria
Signs and Symptoms
Tests and Diagnosis
Drugs and Treatment
What is Heme?
• Acts as an oxygen carrier in the blood 1
• Used in production of hemoglobin, myoglobin &
cytochromes 1
• Made in liver & bone marrow 1
• Structure: Tetrapyrrole ring with iron atom in
the middle 2
Structure of Heme
Figure 1.
Heme. Retrieved 09/20, 2014, from http://wwwnmr.cabm.rutgers.edu/photogallery/proteins/htm/heme.htm
Figure 2.
Diwan, J. (2008). Synthesis of heme. Retrieved
09/20, 2014, from
https://www.rpi.edu/dept/bcbp/molbiochem/
MBWeb/mb2/part1/heme.htm
Heme Synthesis
• 8 Enzymes 4
• Rate limiting
= δ-Aminolevulinate
(ALA) Synthase 4
o Negatively regulated
by heme 5
• Most heme made in
bone marrow for
RBC, but 15% made in
the liver 4
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.
Heme Synthesis
• Porphyrins
o main precursor to
heme 2
• Porphyrin + Iron =
HEME 2
• Build up in
porphyrins  toxic to
tissue 3
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.
Porphyria
• Deficiency in one of the enzymes in the heme
synthesis pathway 3
• Physiological classification – based on where
heme precursors accumulate 1
o Hepatic – in liver 1
o Erythropoietic – in red blood cells 1
• Classification based on clinical symptoms:
▫ Acute porphyria – affects nervous system 1
▫ Cutaneous porphyria – affects skin 1
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.
Acute Intermittent Porphyria (AIP)
• Most common type of acute Porphyria 6
• Autosomal dominant inheritance pattern 6
• Not all patients with AIP mutation show the
disease 6
• Deficiency of
PBG
deaminase
activity 6
King, M. (2014). Acute intermittent porphyria, AIP. Retrieved 09/20, 2014,
from http://themedicalbiochemistrypage.org/aip.php
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.
Porphyria Cutanea Tarda (PCT)
• Most common type of the porphyrias 6
• Can be sporadic and is associated with alcohol,
estrogens, and iron overload. 6
• Minority of patients inherit this type. 6
o Autosomal dominant inheritance pattern 6
• Deficiency of
UROdecarboxylase
activity 6
King, M. (2014). Porphyria Cutanea Tarda, PCT. Retrieved 09/20, 2014,
from http://themedicalbiochemistrypage.org/aip.php
Signs and Symptoms
Acute Porphyria
Cutaneous Porphyria
 Chest/abdominal pain 7
  heart rate & blood
pressure 2
 Muscle weakness, tingling
loss of sensation 7
 Nausea and vomiting 7
 Constipation 7
 Seizures 7
 Urinary retention 7
 Oversensitivity to sun when
skin exposed 7
 Blisters, itching, swelling
skin, and pain 2
  hair growth 2
 Darkening /thickening of
skin 2
Tests and Diagnosis
• Urine Tests
o Ex. Acute Porphyria
• Can detect the porphrin PBG which will usually 
during an acute attack. 3
o Ex. Porphyria
Cutanea Tarda
• Will have orange-red
urine in daylight and it
will look red under UV
light. 3
Tests and Diagnosis
• Stool Tests
o Ex. Porphyria Cutanea Tarda
• Deficiency in URO-decarbxylase shows 
porphyrins. 3
• DNA testing
o Ex. Acute Porphyria
• Check for mutations of enzymes involved in heme
synthesis. 3
** Acute Porphyrias = Commonly misdiagnosed
Treatment for Acute Porphyria
• Panhematin 1
o 3-4 mg once a day 1
o Used to correct heme deficiency in liver and stop
production of porphyrin precursors 1
o Also acts as a mild anti-coagulant 1
• High carbohydrate diet 1
• Last Resort: Liver transplant 3
Treatment for Cutaneous Porphyria
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Avoid sunlight 8
Iron chelation 8
Blood Removal 8
Avoid drinking alcohol 8
Other Treatments
• Heme transfusion 1
• Medication that induce cytochrome p450 have a
chance of causing porphyria attacks 1
• Info for
skit From:
Reference
9
Summary
• What is Heme?
▫ Structure: Tetrapyrrole ring with iron atom in the middle
▫ An oxygen carrier in the blood
▫ Used in production of hemoglobin, myoglobin & cytochromes
• Heme Synthesis
▫ Involves 8 enzymes; ALA Synthase is negatively regulated by heme
• Porphyria
▫ Deficiency in one of the 8 enzymes in the heme synthesis pathway leading to porphyrin
build up
▫ Tests: Urine Test, Stool Test, DNA test
• Acute Porphyria
▫ Ex. Acute Intermittent Porphyria (AIP) -> Deficiency of PBG deaminase activity
▫ Symptoms: Affects nervous system; chest/abdominal pain, heart rate ↑, blood pressure ↑,
nausea, vomiting, constipation, urinary retention
▫ Treatment: Panhematin, high carbohydrate diet, liver transplant
• Cutaneous Porphyria
▫ Ex. Porphyria Cutanea Tarda (PCT) -> Deficiency of URO-decarboxylase activity
▫ Symptoms: Oversensitivity to sun; blisters, swelling, darkening/thickening of the skin,
hair growth ↑
▫ Treatment: Avoid sunlight, iron chelation, blood removal
References
1
2
3
4
5
6
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic
manifestations. Handbook of Clinical Neurology, 120, 839-849.
Mir, M.A. (2014). Porphyria overview. Medscape. Retrieved 09/18, 2014,
from http://emedicine.medscape.com/article/1389981-overview
Balwani, M., & Desnick, R. J. (2012). The porphyrias: Advances in
diagnosis and treatment. Blood, 120(23), 4496-4504.
doi:10.1182/blood-2012-05-423186; 10.1182/blood-2012-05-423186
Phillips, J. D., & Kushner, J. P. (2005). Fast track to the
porphyrias. Nature Medicine, 11(10), 1049-50. doi:
http://dx.doi.org.myaccess.library.utoronto.ca/10.1038/nm10051049
James, M. F. M., & Hift, R. J. (2000). Porphyrias. BJA: International
Journal of Anaesthesia, 85(1), 143-153.
Scarlett, Y., & Brenner, D. (1998). Porphyrias. Journal of Clinical
Gastroenterology, 27(3), 192 - 198.
References
7 National Digestive Diseases Information Clearinghouse.
(2014). Porphyria. Retrieved 09/18, 2014, from
http://digestive.niddk.nih.gov.myaccess.library.utoronto.ca/ddis
eases/pubs/porphyria/index.aspx#treatment
8 Tintle, S., Alikhan, A., Horner, M. E., Hand, J. L., & Davis, D. M. R. (2014).
Cutaneous porphyrias part II: Treatment strategies. International
Journal of Dermatology,53(1), 3-24. doi:10.1111/ijd.12016
9 Mahatthanatrakul, W., Nontaput, T., Ridtitid, W., Wongnawa, M., &
Sunbhanich, M. (2007). Rifampin, a cytochrome P450 3A inducer,
decreases plasma concentrations of antipsychotic risperidone in
healthy volunteers. Journal of Clinical Pharmacy and
Therapeutics, 32(2), 161-167. doi:10.1111/j.1365-2710.2007.00811.x