1. Porphyria and Errors in Heme Metabolism
Jonathan Ko, Michael Latayan,
Patrick Hopper, Yameen Ingar
November 6, 2018
PHM142 Fall 2018
Instructor: Dr. J. Henderson

2. What Are Porphyrias?
Porphyrias are a group of 8 heme synthesis disorders that can cause nerve or skin problems
It is when your cells fail to change body chemicals called porphyrins or porphyrin precursors into heme
Buildup of porphyrin and/or its precursors cause illness
Heme is important; is a major component of both myoglobin and hemoglobin
Also used in the liver for the synthesis of cytochrome P450 (PK drug metabolism)
2 Major Types:
Cutaneous porphyrias (porphyrias affecting the skin)
Sometimes called the Vampire Disease - similar effects to vampire legends
Photosensitivity and shrunken gums
Acute porphyrias (porphyrias affecting the nervous system)
The most common type of porphyria is porphyria cutanea tarda (PCT)
Effects can vary: can do nothing to some but can be life threatening to others
Many people live their lives never knowing they have it

3. Causes
Is mainly hereditary - can be passed from parents to their children
Can be autosomal dominant or recessive, or even X linked, with dominant being the most common
Symptoms do not occur right away; usually people don’t realize they have it until a trigger causes symptoms to appear
Possible Triggers:
Alcohol consumption
Smoking
Sunlight
Stress
Certain medications
Eating disorders
The different types of porphyrias can have different triggers
For example, porphyria cutanea tarda (PCT) has been known to be triggered by HIV, iron or lead accumulation and Hepatitis C

4. Symptoms Symptoms vary in cutaneous and acute porphyria Cutaneous:
Occur continuously
Oversensitivity to sunlight
Blisters on exposed skin → itching and swelling
Acute:
Occur spontaneously or develop with time
Pain in abdomen, chest, limbs, back
Constipation & urinary retention
Muscle weakness and seizures

5. General Diagnosis
Involve blood, urine and stool tests → detect high levels of porphyrin & its precursors, and DNA testing (gene mutations)
Often, due to ambiguity of symptoms acute porphyria is misdiagnosed
Common methods of Acute Porphyria:
PBG - intermediate in porphyrin formation; via urine
Individual acute porphyrias require analysis of urine, plasma and fecal porphyrias
Common methods of Cutaneous Porphyria:
EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy
Whole blood analysis for porphyrin
PBG = Porphobilinogen, which is an intermediate in porphyrin synthesis, is detected via urine test → urine concent. tested via measuring creatinine concentration
Test involves a validated quantitative ion-exchange resin-based method or LC-MS
Cutaneous:
EDTA or (Ethylenediamine tetra acetic acid) blood sample for plasma porphyrin

6. Heme Metabolism & Deficiencies Causing Porphyria

7. Normal Heme Biosynthesis
Glycine & Succinyl-CoA ) ALA Molecules
ALA Synthase (ALAS) PBG Synthase
5 aminolevulinic acid (ALA) Porphobilinogen (PBG)
checked=true

8. Normal Heme Biosynthesis
3) PBG
PBG Deaminase
Tetrapyrol hydroxymethybilane (HMB)
4) HMB
Uro’gen synthase
Uroporphyrinogen (Uro’gen)

9. Normal Heme Biosynthesis
5) Uro’gen
Uroporphyrinogen decarboxylase (UROD)
Coproporphyrinogen (Copro’gen)
6) Copro’gen
Coproporphyrinogen oxidase
Protoporphyrinogen

10. Normal Heme Biosynthesis
7) Protoporphyrinogen
Protoporphyrinogen oxidase
Protoporphyrin IX (PP)
8) Protoporphyrin IX + Ferrous Iron
Ferrochelatase
Heme

12. Types of Porphyria and Deficient Enzyme
- Delta-aminolevulinate-dehydratase deficiency porphyria
- Acute intermittent porphyria
- Hereditary coproporphyria
- Variegate porphyria
- Congenital erythropoietic porphyria
- Porphyria cutanea tarda
- Hepatoerythropoietic porphyria
- Erythropoietic protoporphyria
Deficient enzyme:
→ Delta-aminolevulinic acid dehydratase (liver)
→ Porphobilinogen deaminase (liver)
→ Coproporphyrinogen oxidase (liver)
→ Protoporphyrinogen oxidase (liver)
→ Uroporphyrinogen III cosynthase (b. marrow)
→ Uroporphyrinogen decarboxylase - 90% (liver)
→ Uroporphyrinogen decarboxylase - 90% (b. marrow)
→ Ferrochelatase - 75% (b. marrow)

13. Porphyria Cutanea Tarda (PCT)
Most common type of Porphyria, affecting 1/20,000
Deficiencies in UROD
Three types:
Type 1:
Most common type of PCT
Acquired (Sporadic)
Deficiency of UROD Activity
Only in Liver Cells
Type 2:
Inherited - Autosomal Dominant form
Minority of cases
50% reduction in UROD Activity
Type 3:
Underlying mechanism unknown
Rare

14. Diagnosis & Treatment
Acute Intermittent Porphyria, Porphyria Cutanea Tarda
AIP, , PP

15. Diagnosis - Acute Intermittent Porphyria
Presentation
Healthy young woman with days of severe fatigue and lack of concentration
Severe abdominal pain
Nausea, vomiting, weakness
Analgesics ineffective
Tachycardia, Elevated systole
Elevated porphobilinogen plasma/urine levels
Triad: hyponatremia, abdominal pain, seizure
Colorless urine but light exposure turns it dark
Elevated porphobilinogen in plasma/urine
10-150x normal
not part of normal porphyrin screen
Due to porphobilinogen deaminase deficiency
Deficiency in heme in neuronal cells/build up of ALA (delta aminolevulinic acid)
Lack of antianalgesic response = ppl think psychosomatic pain/drug addict
Autosomal dom.
Environmental factors can trigger
catamenail/medication triggers/reduced calories

16. Treatment - Acute Intermittent Porphyria
Review medications
Administer fluids, antiemetics, analgesics, antiseizure
IV heme (Panhematin)
Decrease porphobilinogen levels
Gene therapy
siRNA of delta-aminolevulinic acid synthase 1
Liver transplant
Meds/environment can trigger
Antiemetic: antibarf
Analgesics: pain
Gene therapy introduce normal working enzyme
siRNA to reduce toxic levels that accumulate of dALA
Liver transplant works too
From Bissell et. al (2017).

17. Diagnosis- Porphyria Cutanea Tarda
Presentation
40 years with skin friability, chronic blister lesions on sun exposed
facial hair on women
urine/plasma porphyrin profile has uroporphyrin & heptacarboxyporphyrin
Excess uroporphyrin turns urine red-brown
photosensitivity: excitation and release = injury to skin
Due to uroporphyrinogen decarboxylase inhibition; leads to build up
Excess hepatic iron plays role

18. Treatment - Porphyria Cutanea Tarda
Iron depletion/chelators
Reduce risk factors
Antimalarials
hydroxychloroquinone/chloroquinone
First point: shown to reduce remission of symptoms
Draw blood frequently A
Hydroxychloroquinones (antimarials)
Helps hepatocytes mobilize porphyrins for urinary excretion
From Bissell et. al (2017).

19. Summary
Porphyrias are a group of 8 heme synthesis disorders in one of the 8 heme biosynthesis pathway enzymes, that can cause nervous system (acute) or skin (cutaneous) problems
Disorders cause porphyrin or porphyrin precursor accumulation, which lead to illness
Mainly hereditary
Generally diagnosed with blood, urine and stool tests: looking for increased levels of porphyrins and their precursors
Porphyria Cutanea Tarda (PCT) is the most common type of cutaneous porphyria
Symptoms - blisters and photosensitivity
Treatments - can prescribe antimalarials

20. Summary cont.

21. References
Besur, S., Hou, W., Schmeltzer, P., & Bonkovsky, H. (2014). Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias. Metabolites, 4(4),
Bissell DM., Anderson KE., Bonkovsky HL. (2017). Porphyrias. N Engl J Med, 377(9),
Bonkovsky, H., Poh-Fitzpatrick, M., Pimstone, N., Obando, J., Di Bisceglie, A., & Tattrie, C. et al. (1998). Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in north
america. Hepatology, 27(6),
National Institution of Diabetes and Digestive and Kidney Diseases. (2014). Porphyria. National Institution of Diabetes and Digestive and Kidney Diseases.
Puy, H., Gouya, L., & Deybach, J. (2010). Porphyrias. The Lancet, 375(9718),
Szlendak, U., Bykowska, K., & Lipniacka, A. (2016). Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria. Advances In Clinical And Experimental
Medicine, 25(2),
Woolf, J., Marsden, J. T., Degg, T., Whatley, S., Reed, P., Brazil, N., … Badminton, M. (2017). Best practice guidelines on first-line laboratory testing for
porphyria. Annals of Clinical Biochemistry, 54(2), 188–198.

22. References (cont.)
Szlendak, U., Bykowska, K., & Lipniacka, A. (2016). Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria. Advances In Clinical And Experimental Medicine, 25(2), doi: /acem/58955
Bonkovsky, H., Poh-Fitzpatrick, M., Pimstone, N., Obando, J., Di Bisceglie, A., & Tattrie, C. et al. (1998). Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in north america. Hepatology, 27(6), doi: /hep
Besur, S., Hou, W., Schmeltzer, P., & Bonkovsky, H. (2014). Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias. Metabolites, 4(4), doi: /metabo