Summary

Porphyria is a disease in which the production of heme is affected. Heme is a component of the protein hemoglobin which carries oxygen in blood. It is produced in the bone marrow and liver and requires eight enzymes. When any step of heme production is blocked, due to a lack of certain enzymes, there is a buildup of intermediate chemicals called porphyrins which causes oxygen depletion.

It is speculated that King George III from England was afflicted by Porphyria. There are two types of porphyria cutaneous porphyrias and acute porphyrias. In acute porphyrias the nervous system is mainly affected and symptoms include: red or brown urine, breathing problems, muscle pain, seizures, and mental changes i.e. hallucinations, disorientation. In cutaneous porphyrias the skin is what is mainly affected and symptoms include: sensitivity to the sun, sudden painful skin redness, blisters, excessive hair growth, and fragile thin skin with color changes.

Most cases of porphyria are inherited rather than acquired. Porphyria is a rare disease that only affects fewer than 200,00 people in the United States. Women are affected more than men and it is seen more in people of Swedish and English heritage. There is no cure to porphyria there are only treatments for symptoms which depend on the type of porphyria the patient has. Treatments for acute porphyria include: an injection of hemin, intravenous sugar, and hospitalization. Treatments for cutaneous porphyria includes: drawing blood to reduce the amount of iron in the body, taking a drug that is used to treat malaria, and vitamin D supplements. Porphyria attacks can also be triggered and it is advised to avoid triggers like medication, alcohol or drugs, fasting and dieting, smoking, and sun exposure.

Normal heme signaling pathway

5-aminolevulic acid (ALA) is formed from Glycine and Succinyl CoA by ALA synthase. 2 molecules of ALA are joined together by the enzyme ALA dehydratase making porphobilinogen (PBG). PBG deaminase polymerizes 4 molecules of PBG making a linear tetrapyrrole hydroxymethylbilane (HMB). HMB then cyclizes and forms uroporphyrinogen (Uro'gen). Uroporphyrinogendecarboxylase (UROD) decarboxylizes Uro'gen and forms coproporphyrinogen (Copro'gen). Coproporphyrinogen oxidase (CPOX) converts Copro'gen to protoporphyrinogen. Protoporphyrinogen oxidase (PPOX) forms protoporphyrin IX (PP) from protoporphyrinogen ferrochelatase inserts a ferrous iron into PP and finally produces heme.

Symptoms

Acute Porphyria

Severe abdominal pain
Pain in your chest, legs or back
Constipation or diarrhea
Nausea and vomiting
Muscle pain, tingling, numbness, weakness or paralysis
Urination problems & Red or brown urine
Mental changes like anxiety, confusion, hallucinations, disorientation or paranoia
Breathing problems
Rapid or irregular heartbeats
High blood pressure
Seizures
Tingling / loss of sensation
Kidney damage (long term)
Liver cancer (long term)
Electrolyte imbalance
Anemia

Cutaneous Porphyria

Sensitivity to the sun and artificial light causing a burning pain
Sudden painful skin redness and swelling
Blisters on exposed skin
Fragile thin skin with changes in color
Itching
Excessive hair growth
Red or brown urine
Electrolyte imbalance
Anemia

Porphyria signaling pathway

The pathway for heme synthesis beings in the mitochondria and uses 8 different enzymes. The pathway moves into the cytoplasm for 3 stages then heme is finally made in the mitochondria. ALAS is the first enzyme and is the rate limiting enzyme which is controlled by negative feedback. Porphyria's occur when there is an over expression of Heme precursor molecules especially ALAS and porphobilinogen in the liver because there is a loss of heme mediated repression. The specific Porphyria is marked next to the enzyme in which there is a decrease in function that causes it. The pathway is not fully understood.

How the symptoms relate to the signaling pathway

The actual pathway in which Porphyria brings on symptoms is poorly understood, however there are some thoughts on what may be occurring. When porphyrins accumulate in the liver, which is where they are produced, they can also diffuse into the blood. They can also be excreted in the urine or deposited into other tissues in the body like the skin for one. If they are deposited in the skin they can absorb light, but they are unable to store the energy produced by the light like other porphyrins for example chlorophyll are able to do. The energy that is not stored then gets released into the skin and causes damage in the form of blisters and scarring which are some of the symptoms given for Cutaneous Porphyria. It is not exactly known how the mechanism of porphyria causes neurologic damage. However, there are hypotheses which include: when ALA levels are elevated, when there are defects in heme synthesis in neural tissue, and when tryptophan and serotonin levels are increased the neurovisceral features of acute porphyria attacks are expressed. Though the mechanism is still unknown ALA has been recognized as a neurotoxin. There are other factors that increase the risk of an attack which include: iron which inhibits the activity of UROD, excessive alcohol intake which can cause UROD deficiency and lead to the formation of damaging forms of oxygen in hepatocytes, Hepatitis C though the mechanism for how this increases risk in attacks is unknown, and estrogens however the mechanism is unknown.

Treatment for Porphyria

There is no cure for porphyria as much is still not known about the disease, but there are a combination of drugs that can be used to treat the symptoms. Drugs that are used to treat pain in Acute Porphyria are Demerol, Hydromorphone, Morphine, and Fentanyl. To treat nausea and vomiting Chlorpromazine can be used. If the patient is experiencing seizures Gabapentin may be used. If the patient is experiencing attacks with mild pain Carbohydrate loading of IV Dextrose may be used to down regulate ALA-Synthase and its protein. If the patient is experiencing prolonged attacks Panhematin a Hemin injection may be administered to limit the rate of heme biosynthesis by inhibiting ALAS1. To treat Cutaneous Porphyria a phlebotomy and aphaeresis may be preformed to remove excess iron in the blood. Skin protection and avoiding the sun is advised. Drugs to treat malaria may be used to absorb excess porphyrins and help patients to get rid of the porphyrins more quickly. Avoiding triggers to prevent attacks. Some of the triggers are alcohol, stress, hormonal drugs, and sunlight. Vitamin D can be supplemented since sun exposure is to be avoided. A liver transplant can be done for patients with Acute Intermittent Porphyria and Variegate Porphyria if symptoms persist. A bone marrow transplant can be done for patients with Erythropoietic Porphyria if symptoms persist. A splenectomy in patients with Congenital Erythropoietic Porphyria. Individuals with Acute Porphyria can also consume high levels of carbohydrates in their diet because glucose has the ability to decrease porphyrin synthesis in the liver.

Side effects of Treatment

Some of the side effects of treatment include inflammation around the injection site when a haem injection is administered. Rarely will it interfere with blood clotting and cause an allergic reaction. Other side effects for the medication prescribed to treat the pain include addiction to the pain medication, slow heartbeat, pain burning or swelling near the IV site. Drowsiness, dizziness, light headedness and blurred vision are side effects of the medication for nausea and vomit.

Citations

Porphyria. (2015, April 12). Retrieved from http://www.porphyriafoundation.com/about-porphyria/history-of-porphyria

Besur, S., Hou, W., Schmeltzer, P., & Bonkovsky, H. L. (2014, December). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279155/#!po=0.340136

Porphyrin and Heme Metabolism. (n.d.). Retrieved from https://themedicalbiochemistrypage.org/heme-porphyrin.php

Tidy, C. (n.d.). Porphyria | Health. Retrieved from https://patient.info/health/porphyria-leaflet

Groß, U., Puy, H., Jacob, K., Deybach, J. C., Kremer, J., & Doss, M. O. (2006). Biochemical compared to molecular diagnosis in acute intermittent porphyria.Journal of Inherited Metabolic Disease, 29(1), 157-61. http://dx.doi.org.ezproxy.fgcu.edu/10.1007/s10545-006-0155-9

Singal, A. K., Parker, C., Bowden, C., Thapar, M., Liu, L., & McGuire, B. M. (2014). Liver transplantation in the management of porphyria. Hepatology, 60(3), 1082-9. http://dx.doi.org.ezproxy.fgcu.edu/10.1002/hep.27086

Tollånes, M. C., Aarsand, A. K., & Sandberg, S. (2011). Excess risk of adverse pregnancy outcomes in women with porphyria: A population-based cohort study. Journal of Inherited Metabolic Disease, 34(1), 217-23. http://dx.doi.org.ezproxy.fgcu.edu/10.1007/s10545-010-9231-2

Millward, L. M., Kelly, P., King, A., & Peters, T. J. (2005). Anxiety and depression in the acute porphyria’s. Journal of Inherited Metabolic Disease, 28(6), 1099-107. http://dx.doi.org.ezproxy.fgcu.edu/10.1007/s10545-005-4561-1

Siegesmund, M., van Tuyll, v. S., Poblete-Gutiérrez, P., & Frank, J. (2010). The acute hepatic porphyrias: Current status and future challenges. Best Practice & Research, 24(5), 593-605. http://dx.doi.org.ezproxy.fgcu.edu/10.1016/j.bpg.2010.08.010

Porphyria