1. 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

2. Outline What is Heme? Heme Synthesis Porphyria Signs and Symptoms Tests and Diagnosis Drugs and Treatment

3. 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

4. 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.

5. 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 Heme Synthesis Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.

6. Porphyrins o main 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.

7. 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

8. Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.

9. 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

10. Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849.

11. 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 URO- decarboxylase activity 6 King, M. (2014). Porphyria Cutanea Tarda, PCT. Retrieved 09/20, 2014, from http://themedicalbiochemistrypage.org/aip.php

12. Signs and Symptoms Acute PorphyriaCutaneous 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

13. 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

14. 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

15. 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

16. Treatment for Cutaneous Porphyria Avoid sunlight 8 Iron chelation 8 Blood Removal 8 Avoid drinking alcohol 8

17. Other Treatments Heme transfusion 1 Medication that induce cytochrome p450 have a chance of causing porphyria attacks 1

19. Info for skit From: Reference 9

20. 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

21. References 1Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, 839-849. 2Mir, M.A. (2014). Porphyria overview. Medscape. Retrieved 09/18, 2014, from http://emedicine.medscape.com/article/1389981-overview 3Balwani, 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 4Phillips, 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- 1049 5James, M. F. M., & Hift, R. J. (2000). Porphyrias. BJA: International Journal of Anaesthesia, 85(1), 143-153. 6Scarlett, Y., & Brenner, D. (1998). Porphyrias. Journal of Clinical Gastroenterology, 27(3), 192 - 198.

22. References 7National 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 8Tintle, 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 9Mahatthanatrakul, 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