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Porphyrias and Errors In Heme MetabolismBy: Maria Moreno, Jin-Hee Park,Seo Youn Kim and Newton Wong
September 23, 2014 PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson
Outline
•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
Heme. Retrieved 09/20, 2014, from http://www-nmr.cabm.rutgers.edu/photogallery/proteins/htm/heme.htm
Diwan, J. (2008). Synthesis of heme. Retrieved 09/20, 2014, from https://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/heme.htm
Figure 1. Figure 2.
•8 Enzymes 4
•Rate limiting = δ-Aminolevulinate (ALA) Synthase 4
oNegatively regulated by heme 5
•Most heme made in bone marrow for RBC, but 15% made in the liver 4
Heme Synthesis
Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.
•Porphyrins omain precursor to
heme 2
•Porphyrin + Iron = HEME 2
•Build up in porphyrins toxic to tissue 3
Heme Synthesis
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
oHepatic – in liver 1
oErythropoietic – 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
oAutosomal dominant inheritance pattern 6
•Deficiency of URO-decarboxylase activity 6
King, M. (2014). Porphyria Cutanea Tarda, PCT. Retrieved 09/20, 2014, from http://themedicalbiochemistrypage.org/aip.php
Signs and SymptomsAcute 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
oEx. Acute Porphyria• Can detect the porphrin PBG which will
usually during an acute attack. 3
oEx. Porphyria Cutanea Tarda
• Will have orange-red urine in daylight and it will look red under UV light. 3
Tests and Diagnosis•Stool Tests
oEx. Porphyria Cutanea Tarda• Deficiency in URO-decarbxylase shows
porphyrins. 3
•DNA testing oEx. 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
oUsed to correct heme deficiency in liver and stop production of porphyrin precursors 1
oAlso acts as a mild anti-coagulant 1 •High carbohydrate diet 1
•Last Resort: Liver transplant 3
Treatment for Cutaneous Porphyria •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
References1 Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic
manifestations. Handbook of Clinical Neurology, 120, 839-849.2 Mir, M.A. (2014). Porphyria overview. Medscape. Retrieved 09/18,
2014, from http://emedicine.medscape.com/article/1389981-overview
3 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-2012-05-4231864 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/nm1005-
10495 James, M. F. M., & Hift, R. J. (2000). Porphyrias. BJA: International
Journal of Anaesthesia, 85(1), 143-153.6 Scarlett, Y., & Brenner, D. (1998). Porphyrias. Journal of Clinical
Gastroenterology, 27(3), 192 - 198.
References7 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#treatment8 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