Acute intermittent porphyria

Definitions & Key takeaways

Acute intermittent porphyria is a rare genetic disorder in which there is a deficiency of a heme biosynthetic enzyme called hydroxymethylbilane synthase (HMBS). Without HMBS, the synthesis of heme is impaired, which results in the accumulation of metabolites delta-aminolaevulinic (ALA), and porphobilinogen (PBG), which are potentially toxic.

Signs and symptoms of acute intermittent porphyria usually begin between the ages of 20 and 40. They can include abdominal pain, vomiting, constipation, seizures, mental confusion, signs of peripheral neuropathy, and dark urine.

Chapters:

Watch video only

Introduction0:00–0:23

Acute intermittent porphyria is a rare autosomal dominant disorder that belongs to a family of disorders called porphyria.
These disorders all affect the production of heme which is a major component of red blood cells. Now, heme synthesis is also called porphyrin synthesis and when halted, it results in the buildup of one of its precursor molecules.
In order to better understand acute intermittent porphyria, we need to first take a look at hemoglobin, the main protein within red blood cells that’s responsible for carrying oxygen.

Physiology0:23–2:25

Now hemoglobin is made up of hemes and globins. There are 4 globin subunits, typically two alpha and two beta, and each one has its own heme group.
This heme is a large molecule that’s made up of four pyrrole subunits that forms a ring, and this structure is called a porphyrin.
In the middle, there is an ionically bonded iron 2+ and the iron is what binds to and carries the oxygen molecule. So each hemoglobin can carry four oxygen molecules when it’s fully saturated.
The process of heme synthesis occurs both within the mitochondria and the cytosol of a cell and requires multiple enzymes to catalyze the numerous steps.
It starts in the mitochondria where succinyl CoA binds to glycine via delta-ALA synthase to produce delta-aminolevulinic acid, or ALA.
Then, in the cytosol, delta-aminolevulinic acid is converted to porphobilinogen, or PBG, via delta-ALA dehydratase. From there, four molecules of porphobilinogen condense together to form hydroxymethylbilane with the help of porphobilinogen deaminase.
Note that porphobilinogen deaminase is sometimes called uroporphyrinogen I synthase or hydroxymethylbilane synthase, or HMBS for short.
Afterwards, hydroxymethylbilane is converted to uroporphyrinogen III and catalyzed to coproporphyrinogen III via uroporphyrinogen III cosynthase and uroporphyrinogen decarboxylase, respectively.
Next, coproporphyrinogen III is brought back into the mitochondria and converted into protoporphyrinogen IX by coproporphyrinogen oxidase.
Protoporphyrinogen IX is converted to protoporphyrin IX by protoporphyrinogen oxidase. Lastly, an iron molecule is added to protoporphyrin IX via the enzyme ferrochelatase, and viola!
We got ourselves a completed heme!So, the porphyria disorders occur when one of the enzymes in the heme synthesis pathway is deficient, which causes a decrease in heme synthesis and a buildup of metabolites formed in the earlier steps of the pathway.

Pathophysiology2:25–4:00

Now individuals with acute intermittent porphyria have a mutation of the HMBS gene which codes for the enzyme porphobilinogen deaminase.
Without this enzyme, porphobilinogen cannot be converted to hydroxymethylbilane and the heme synthesis pathway can’t continue.
Furthermore, it causes the buildup of the earlier metabolites like porphobilinogen and aminolevulinic acid, which can be toxic to the body.The majority of individuals with the HMBS gene mutation and a deficiency of porphobilinogen deaminase are asymptomatic.
Only around 10% of individuals, typically young adult women, are affected by what is known as acute attacks, which are caused by certain triggers.
Anything that stimulates increased heme production synthesis can be considered a trigger since it will inevitably cause buildup of porphobilinogen and aminolevulinic acid.
Some examples of these triggers include excessive alcohol consumption, starvation and certain medications that increase cytochrome p450 protein.
This protein also contains heme and is used to break down many medications like barbiturates, antiepileptics, and oral contraceptives.Now, the acute attacks are likely due to the build up of the toxic metabolites.
Aminolevulinic acid, in particular, is the most likely culprit since it could cross the blood brain barrier and affect the central, autonomic, and peripheral nervous systems.
In the central nervous system it could cause psychological problems like anxiety or psychosis, but it can also cause seizures, delirium, and even coma.
Toxic metabolites also affect the autonomic nervous system regulating gastrointestinal motility, and this can cause abdominal pain, constipation, and vomiting.

Symptoms4:00–5:05

In the peripheral nervous system, they can cause peripheral neuropathy and paresthesia which is numbness and prickling sensations, particularly in the legs and feet.
So, the symptoms of acute intermittent porphyria can be remembered with the 4 P's mnemonic: Painful Abdomen, Polyneuropathy, Psychological disturbances, and Port-wine colored urine.
This last one is caused by the excess porphobilinogen being excreted in the urine. Initially the urine is colorless, but if exposed to light the porphobilinogen oxidizes and turns a reddish, wine color.
The last important thing to keep in mind is that acute intermittent porphyria can be distinguished from the many other porphyrias by the fact that it does not cause any photosensitive cutaneous symptoms like skin blistering when exposed to sunlight.To diagnose acute intermittent porphyria, a urinalysis is conducted which typically shows an elevation of porphobilinogen at least five times greater than normal levels.
The diagnosis is confirmed by measuring erythrocyte porphobilinogen deaminase activity.Glucose and heme are the treatments for acute intermittent porphyria as they inhibit aminolevulinic acid synthase, the first enzyme involved in heme synthesis.

Diagnosis5:05–5:21

In the United States, heme is administered as a lyophilized powder injection of hematin, but in most other parts of the world treatment is usually administered intravenously as heme arginate.All right, as a quick recap...acute intermittent porphyria is an autosomal dominant disorder caused by a deficiency of the enzyme porphobilinogen deaminase in the heme synthesis pathway.

Treatment5:21–5:42

This results in the buildup of porphobilinogen and aminolevulinic acid. Although it is usually asymptomatic, an acute attack can be triggered by certain medications, alcohol, and starvation.
These symptoms may include painful abdomen, polyneuropathy, psychological disturbances, and port-wine colored urine. The main methods of treatment are glucose and heme.

Review5:42–6:12

deficiency of the enzyme porphobilinogen deaminase in the heme synthesis pathway This results in the build-up of porphobilinogen and amino Levulan acid Although it's usually asymptomatic an acute attack can be triggered by certain medications alcohol and starvation These symptoms might include painful abdomen polyneuropathy psychological disturbances and poor wine colored urine The is a is a is a the the of the of the