1- WHAT are porphyrias

heme basic
Heme

The porphyrias are a group of rare metabolic diseases in which chemical substances called porphyrins accumulate, leading to either skin changes or neurological symptoms or sometimes both.

In humans, porphyrins are the main precursors of heme: deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme, that plays a central role in cellular metabolism as essential constituent of hemoglobin, myoglobin, catalase, peroxidase and – mostly – on P450 liver cytochrome, essential to expel toxins. 

The exact prevalence of porphyria is unknown, but it probably ranges from 1 in 500 to 1 in 50,000 people worldwide. Overall, porphyria cutanea tarda is the most common type of porphyria. For some forms of porphyria, the prevalence is unknown because many people with a genetic mutation associated with the disease never experience signs or symptoms.

Acute intermittent porphyria is the most common form of acute porphyria in most countries. It may occur more frequently in northern European countries, such as Sweden, and in the United Kingdom. Another form of the disorder, hereditary coproporphyria, has been reported mostly in Europe and North America. Variegate porphyria is most common in the Afrikaner population of South Africa; about 3 in 1,000 people in this population have the genetic change that causes this form of the disorder.

Dr. Nick Lane MD – on Scientific American – wrote that “all forms of porphyria have one thing in common: they are the result of abnormalities in the biosynthesis of heme. Heme, a component of hemoglobin which makes by ‘oxygen carrier’, is produced by a sequence of reactions in eight stages, as in an assembly line in a factory. Each step is catalysed by a separate enzyme. If one of these eight steps fails due to an inherited genetic mutation or an environmental toxin, then, the entire assembly line jams.

The products of the previous phases, intermediate porphyrin, can grow up to toxic levels. These porphyrins accumulate in the organs and skin (ed. For skin forms) before being excreted in faeces and urine (which can become a burgundy color). Exposed to light, the porphyrins can be caustic and destroy surrounding tissue.
Porphyrins are activated to light chemical substances that can be used to combat diseases such as tumors. But they have a dark side: when the ‘wrong’ forms accumulate in the body causing a disease called porphyria.” 

The Porphyrias are always systemic and never topical.
For the emergency management
the adoption of a toxicological approach is vital, avoiding to confuse the variable and systemic symptoms as if they were somatizations; in the of long-term management it is essential to maintain a internal medicine approach and not  to refer – merely and singularly -to gastroenterology, hepatology and dermatology.

Porphyrias are classified in two ways, by symptoms and by pathophysiology. If physiologically, porphyrias are classified as hepatic or erythropoietic based on the sites of accumulation of heme precursors (but not necessarily the ‘defective organs’), the different symptomatology is easily clear:

  • Acute porphyrias primarily cause nerves and liver involvement, often with severe abdominal pain, vomiting, periferic neuropathies, orbital pain, hypertension and – in some carriers  – mental disturbances.
    The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP).
    The most severe episodes (acute attacks) may involve neurological complications because the systemic action of neurotoxic substances by the defected heme synthesis. It is not proved that carriers with no acute attacks are symptomless.
  • Cutaneous porphyrias cause skin problems, often after exposure to sunlight, because porphyrins react with light.
    The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP).
    None of these are associated with acute attacks; their primary or only manifestation is with skin disease. Sun protection eliminates the symptoms but not the disease.

The symptoms are wide and varied, being in fact an endogenous neurological poisoning with metabolic disorders, and, not surprisingly, Dr. Helen L. Crimliskha titled with the name of “the little imitator” (Journal of Neurology, Neurosurgery, and Psychiatry Vol 62, 319 Ð 328, 1997).

As well described by Porphyria Association inc. Australia, “the porphyrias are a collection of disorders of haem synthesis, each resulting from a separate enzyme deficiency in the pathway.

  • Broadly, the build up of haem precursors cause neuro-visceral problems and /or skin reactivity to light.
  • Active Porphyria is extremely painful and can be very debilitating.
  • The porphyrias can become progressive degenerative disorders.
  • Currently the main aim is prevention strategies to keep them latent.
  • Once triggered an episode can escalate into a biofeedback loop causing toxic build up of porphyrins.
  • Porphyria has been mistaken for: somatisation disorders, Guillain Barre, growing pains, eczema, epilepsy, MS, dermatology, depression, acute appendicitis, chronic fatigue, Parkinson’s, Irritable Bowel syndrome and many, many more.”

The two most common types are porphyria acute intermittent porphyria ( PAI ) and porphyria cutanea tarda ( PCT ) . The prevalence of each is about 1 / 10,000 , but the prevalence varies greatly between regions and ethnic groups.”  (source Merck ‘s Manual for Professionals)

This means that in a region or a city of 1,000,000 inhabitants , the probable number of carriers is about 100 people, if we talk about territories directly involved by Viking / Norman / Dutch spread. For an “unchecked disease” so serious like porphyrias, it is a luck if many of them appear to be asymptomatic or very low symptomatic, but it could be a blame if a part of those are treated for anything but not porphyria.

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