Acute Intermittent Porphyria – causes, symptoms, diagnosis, treatment, pathology

Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
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much more. Try it free today! 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 result in the buildup of one of its precursors 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. 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 an ionically bond 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 begins 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. 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 classic 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 also can cause seizures, delirium,
and even coma. Toxic metabolites also affect the autonomic
nervous system regulating gastrointestinal motility, and this can causes abdominal pain,
constipation, and vomiting. 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 other many porphyrias by the fact
that it doesn’t cause any photosensitive cutaneous symptoms, or 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. 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. 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.


  1. Hi @Osmosis today my husband was diagnosed with Primary progressive aphasia. Could you maybe do a video about it?

  2. Darlings, could you PLEASE do a subset of this video and describe "Doss Porphyria". It is very rare. In it there is NO bilinogen found in the urine. A medical oddball worth learning about. Especially because it is often undiagnosed, and doctors need to be more aware of it.

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