Porphyrias and Errors In Heme Metabolism

1. Porphyrias and Errors In Heme Metabolism By: Maria Moreno, Jin-Hee Park, SeoYoun 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 & cytochromes1 • Made in liver & bone marrow 1 • Structure: Tetrapyrrole ring with iron atom in the middle 2

4. Structure of Heme Figure 1. 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. Retrieved 09/20, 2014, from http://www-nmr.cabm.rutgers.edu/photogallery/proteins/htm/heme.htm

5. Heme Synthesis • 8 Enzymes 4 • Rate limiting =  δ-Aminolevulinate (ALA) Synthase4 • Negatively regulated by heme5 • 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.

6. Heme Synthesis • Porphyrins • main precursor to heme2 • 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.

7. Porphyria • Deficiency in one of the enzymes in the heme synthesis pathway 3 • Physiological classification – based on where heme precursors accumulate 1 • Hepatic – in liver 1 • Erythropoietic– in red blood cells 1 • Classification based on clinical symptoms: • Acute porphyria– affects nervous system 1 • Cutaneousporphyria– 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 Porphyria6 • Autosomal dominant inheritance pattern 6 • Not all patients with AIP mutation show the disease 6 • Deficiency of PBGdeaminaseactivity 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. PorphyriaCutaneaTarda (PCT) • Most common type of the porphyrias6 • Can be sporadic and is associated with alcohol, estrogens, and iron overload. 6 • Minority of patients inherit this type. 6 • Autosomal dominant inheritance pattern 6 • Deficiency of URO-decarboxylaseactivity 6 King, M. (2014). PorphyriaCutaneaTarda, PCT. Retrieved 09/20, 2014, from http://themedicalbiochemistrypage.org/aip.php

12. Signs and Symptoms

13. Tests and Diagnosis • Urine Tests • Ex. Acute Porphyria • Can detect the porphrin PBG which will usually  during an acute attack. 3 • Ex. PorphyriaCutaneaTarda • Will have orange-red urine in daylight and it will look red under UV light.3

14. Tests and Diagnosis • Stool Tests • Ex. PorphyriaCutaneaTarda • Deficiency in URO-decarbxylase shows  porphyrins. 3 • DNA testing • Ex. Acute Porphyria • Check for mutations of enzymes involved in heme synthesis.3 • ** Acute Porphyrias = Commonly misdiagnosed

15. Treatment for Acute Porphyria • Panhematin1 • 3-4 mg once a day 1 • Used to correct heme deficiency in liver and stop production of porphyrin precursors 1 • Also acts as a mild anti-coagulant 1 • High carbohydrate diet 1 • Last Resort: Liver transplant 3

16. Treatment for CutaneousPorphyria • 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. PorphyriaCutaneaTarda (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 • 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/nm1005- 1049 • 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.

22. References • 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 • Tintle, S., Alikhan, A., Horner, M. E., Hand, J. L., & Davis, D. M. R. (2014). Cutaneousporphyrias part II: Treatment strategies. International Journal of Dermatology,53(1), 3-24. doi:10.1111/ijd.12016 • 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