Approach to Porphyria

Heme is an essential molecule that carries out critical functions necessary for aerobic life.

It's the key component of hemoglobin that carries oxygen in our blood, and it's also vital for the function of cytochrome enzymes in the liver.

Heme is synthesized through eight sequential enzymatic steps, beginning in the mitochondria, moving to the cytoplasm, and finishing back in the mitochondria.

The pathway starts when glycine and succinyl-CoA combine to form delta-amino levulinic acid, or ALA, through the enzyme ALA synthase.

This can be remembered as alas, because you rue the diagnosis of porphyria or having to study for it.

ALA is then converted to porphobilinogen, or PBG.

These early precursors continue through six more steps until finally, iron is inserted into protoporphyrin IX to create heme.

Here's the critical part.

Heme regulates its own production through negative feedback.

When heme levels are adequate, this suppresses the first and rate-limiting enzyme in the pathway, ALA synthase, preventing overproduction of heme precursors.

Porphyria occurs when there's a defect in one of these eight enzymes.

The specific enzyme that's defective determines which type of porphyria develops and what symptoms occur.

When an enzyme is deficient, the intermediate upstream of that blocked step accumulates.

At the same time, reduced heme production also releases the brake on ALA synthase, further driving production of upstream toxic precursors.

There are eight types of porphyria, but they fall into two main categories.

The acute hepatic porphyrias, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and ALA dehydratase deficiency porphyria, are characterized by the accumulation of the neurotoxic precursors ALA and PBG.

These cause acute neurovisceral attacks.

The cutaneous porphyrias, like porphyria cutanea tarda and erythropoietic protoporphyria, involve the accumulation of photosensitizing porphyrins that cause severe skin reactions to sunlight.

Acute intermittent porphyria is the most common acute type, affecting approximately one in a hundred thousand people with symptoms.

While genetic mutations associated with this condition are relatively common, about one in one thousand six hundred people carry the gene, only about 1% actually develop symptoms.

Porphyria cutanea tarda, a cutaneous porphyria, holds the title as the most common porphyria overall, and it is at least in part an acquired disease.

Roughly 80% of cases are purely sporadic, driven by environmental triggers that reduce uroid enzyme activity, like alcohol use, hepatitis C, iron overload, and estrogen exposure, rather than an inherited enzyme deficiency.