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Iron deficiency anemia
Anemia of chronic disease
Hemolytic disease of the newborn
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Autoimmune hemolytic anemia
Pyruvate kinase deficiency
Paroxysmal nocturnal hemoglobinuria
Sickle cell disease (NORD)
Anemia of chronic disease
Folate (Vitamin B9) deficiency
Vitamin B12 deficiency
Acute intermittent porphyria
Porphyria cutanea tarda
Vitamin K deficiency
Immune thrombocytopenic purpura
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Von Willebrand disease
Disseminated intravascular coagulation
Antithrombin III deficiency
Factor V Leiden
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Polycythemia vera (NORD)
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Langerhans cell histiocytosis
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Microcytic anemia: Pathology review
Non-hemolytic normocytic anemia: Pathology review
Intrinsic hemolytic normocytic anemia: Pathology review
Extrinsic hemolytic normocytic anemia: Pathology review
Macrocytic anemia: Pathology review
Heme synthesis disorders: Pathology review
Coagulation disorders: Pathology review
Platelet disorders: Pathology review
Mixed platelet and coagulation disorders: Pathology review
Thrombosis syndromes (hypercoagulability): Pathology review
Lymphomas: Pathology review
Leukemias: Pathology review
Plasma cell disorders: Pathology review
Myeloproliferative disorders: Pathology review
Acute intermittent porphyria
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Tanner Marshall, MS
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.
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.
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