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 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 nmr.cabm.rutgers.edu/photogallery/proteins/htm/heme.htm Diwan, J. (2008). Synthesis of heme. Retrieved 09/20, 2014, from MBWeb/mb2/part1/heme.htm Figure 1.Figure 2.

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,

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,

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,

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

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

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

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

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 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 1Tracy, J., & Dyck, P. (2014). Porphyria and its neurologic manifestations. Handbook of Clinical Neurology, 120, Mir, M.A. (2014). Porphyria overview. Medscape. Retrieved 09/18, 2014, from 3Balwani, M., & Desnick, R. J. (2012). The porphyrias: Advances in diagnosis and treatment. Blood, 120(23), doi: /blood ; /blood Phillips, J. D., & Kushner, J. P. (2005). Fast track to the porphyrias. Nature Medicine, 11(10), doi: James, M. F. M., & Hift, R. J. (2000). Porphyrias. BJA: International Journal of Anaesthesia, 85(1), Scarlett, Y., & Brenner, D. (1998). Porphyrias. Journal of Clinical Gastroenterology, 27(3),

References 7National Digestive Diseases Information Clearinghouse. (2014). Porphyria. Retrieved 09/18, 2014, from 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), doi: /ijd 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), doi: /j x