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