Acute intermittent porphyria
AssessmentsAcute intermittent porphyria
Acute intermittent porphyria
USMLE® Step 1 style questions USMLE
A 30-year-old woman presents to the emergency department for evaluation of acute abdominal pain. The pain developed a day ago and has been constant, diffuse, and 7/10 in intensity. She has also experienced nausea, vomiting, a tingling sensation in the bilateral hands, as well as painless, dark-red urine. The patient had similar episodes in the past following the consumption of alcohol. Past medical history is significant for generalized anxiety disorder, depression, and pelvic inflammatory disease. She is currently sexually active with one male partner and does not use contraception. Temperature is 37.0°C (98.6°F), pulse is 103/min, respirations are 18/min, and blood pressure is 138/78 mmHg. Physical examination reveals a soft, nontender, and nondistended abdomen. Neurological examination shows decreased sensation in the bilateral hands. Which of the following is the most likely cause of this patient’s condition?
Acute intermittent porphyria exam links
Content Reviewers:Yifan Xiao, MD
Contributors:Tanner Marshall, MS, Evan Debevec-McKenney
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. 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. 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.
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.
- "Harrison’s principles of internal medicine" McGraw Hill (2018)
- "Current Medical Diagnosis and Treatment 2020" McGraw Hill (2020)
- "Physiology, pathophysiology, and clinical management 8th Ed" Elsevier (2018)
- "Bates' Guide to Physical Examination and History Taking" LWW (2016)
- "Robbins Basic Pathology" Elsevier (2017)
- "Porphyrias" The Lancet (2005)
- "Clinically Important Features of Porphyrin and Heme Metabolism and the Porphyrias" Metabolites (2014)