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About Porphyria

 Current research indicates that porphyria is a group of 8 different diseases in which there is either a partial deficiency of a heme biosynthesis pathway's enzyme, that occurs in five of the porphyria's: Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), Porphyria Cutanea Tarda (PCT), Erythropoietic ProtoPorphyria (EPP), or a 75% or greater loss of the enzyme in Congenital Erythropoietic Porphyria (CEP), and ALAD Porphyria (ALAD) and Hepatoerythropoietic Porphyria (HEP) (a dual version of PCT), or an excess of the enzyme in one porphyria, X linked ProtoPorphyria, in which one of the enzymes in the heme pathway doesn’t work properly because the enzyme is either deficient (all except X Linked) or excessive (X Linked) (National Organization for Rare Diseases). There are  2 and possibly many more known sub types of porphyria so far, HEP, a dual PCT, and Chester Porphyria a VP/ AIP hybrid. PCT alone has 3 different versions in addition to HEP. 

Heme is a combination of iron and protoporphyrin IX which is essential for the function of all cells requiring oxygen and is made in every cell of the body, but mainly in the bone marrow and the liver. 

The two current classifications of porphyria are: acute hepatic porphyria (AHP), and erythropoietic porphyria (EP).  Four are acute hepatic porphyria's: AIP, HCP, VP, and ALAD-P, and five are erythropoietic porphyria's: CEP, PCT, HEP, EPP, and X Linked Protoporphyria.

 

The acute types: AIP, HCP, VP, and ALAD-P, may have life endangering attacks for which medical treatment is absolutely necessary, and the Erythropoietic and Acute types are also at an increased risk of a certain types of cancer, Skin Cancer and a Liver cancer called Hepatocellular Carcinoma, annual screenings are recommended for the liver starting at the age of 50, and regular skin cancer screenings by a dermatologist.

While the Erythropoetic Porphyria's always have skin sensitivity to UV (Sun) and fluorescent lighting, some milder cases of EPP have been discovered later in life and PCT may never manifest, or may manifest much later in life.  Making this even more complicated is that two of the Acute Porphyria's, HCP, and VP, can also have skin involvement such as blistering in some patients,  and other skin issues (redness, scabbing, peeling, light or dark spots, excess hair, or hair loss), which can range from mild to severe and may not manifest until later on, however about 70% of HCP has no skin blistering.

The types of acute hepatic porphyria (AHP) are Aminolevulinic Acid Dehydratase Porphyria (ALAD-P), Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), and Variegate Porphyria (VP). All of the acute Hepatic Porphyria's are enzyme losses of the corresponding enzyme to the porphyria associated with the heme biosynthetic chain, AIP is PBGD, ALAD is ALAD, HCP is CPOX, and VP is PPOX.  Unfortunately in the U.S. currently only AIP, and ALAD-P, have enzyme testing, the other two types, HCP, and VP, may be much harder and take longer to diagnose, and absolutely require fractionated fecal porphyrins (Blake, Fecal Coproporphyrin Isomers in HCP), plasma fluorescence (University Cape Town, Porphyria), and PBGD enzyme testing ( ...AIP in 196 Patients..), because these two types, HCP, and VP, are documented to not have urinary elevations in ALA/ PBG during life threatening attacks (Hematin treatment of Acute Porphyria, Peterson, 1976) (Janus, 2017). Unlike AIP, which is well documented in Adults, to have elevations in urine PBG, and or ALA, outside of attacks, and, in asymptomatic patients, in more than 60% of carriers, particularly those who had prior attacks ( ...Acute Intermittent Porphyria in 196 Patients.., Kaupinnen, 2002). 

The types of Erythropoietic Porphyria are: Congenital Erythropoietic Porphyria (CEP), which is extremely uncommon, Porphyria Cutanea Tarda (PCT), which is currently the most common U.S. porphyria, Hepatoerythropoietic porphyria (HEP) which is a dual version of PCT, Erythropoietic Protoporphyria (EPP), and X-linked Protoporphyria (XLPP). X linked is a new porphyria which was discovered only a few years ago, and we expect there to be more porphyria's will be discovered in the very near future.

Three of the Acute Porphyria's AIP, HCP, and VP, are autosomal dominant, they are inherited from one parent, however patients with dual versions of the same type are documented,  and children of related parents (cousins) may have a dual version of the same genetic porphyria mutation, often rendering the child incredibly ill,  and in immediate need of testing, diagnosis, and treatment.

It was thought before that patients only had "attacks" or crises, it is now known that some patients have chronic signs and symptoms (Alnylam, Givorsiran drug trial).

 

ALAD Porphyria is autosomal recessive, meaning it was a inherited from both parents, and they have roughly a 95% enzyme loss, but since ALAD is so heavily expressed throughout the body it is thought that ALAD can have a more severe enzyme loss than the other Acute Porphyria's. There are very few known ALAD cases that have been discovered world wide, possibly due to the lack of testing, however about 2% of the population is thought to have a 50% loss of ALAD enzyme, and while this population is not currently classified as having porphyria, more research is always needed into these and all patients.  

Autosomal dominance in the Erythropoietic porphyria's

Porphyria Cutanea Tarda is a 50% loss of the UROD enzyme, and the only Autosomal Dominant Erythropoetic porphyria. Other factors may trigger the onset of symptoms, however there is not a lot understood about the actual mechanism of disease manifestation certain factors may contribute to the patient becoming symptomatic alcohol consumption, usage of estrogens, and excess iron which can accumulate in the Liver.

Autosomal recessive

EPP (a genetic mutation and a polymorphism) best tested for by testing the protoporphyrin in the plasma, or red blood cells, which can find both EPP or X-Linked Protoporphyria. Sun Light, or Fluorescent light, may trigger redness, pain, and itching and less commonly scabbing. The patients may have gall bladder issues, liver issues, and low iron.  

HEP is a dual version of PCT,  and CEP is also autosomal dominant very severe and quite rare porphyria. 

 

 

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