Heme synthesis disorders: Pathology review

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Heme synthesis disorders: Pathology review


Coagulation disorders


Vitamin K deficiency

Leukemoid reaction

Leukemoid reaction


Heme synthesis disorders: Pathology review

USMLE® Step 1 questions

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USMLE® Step 1 style questions USMLE

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A 45-year-old man presents to the office for evaluation of a blistering skin rash. He was out in the sun with his family at a baseball game several days ago. Later that evening, he developed a severe blistering rash on the forearms, hands, neck, and legs. He has tried over-the-counter topical emollients but to little effect. The patient has had similar rashes in the past that eventually self-resolved. The first of such episodes occurred around 10-years ago. Past medical history is also significant for hyperlipidemia and chronic hepatitis C virus infection. He does not consume alcohol, tobacco, or illicit substances. Vitals are within normal limits. Physical examination reveals small ruptured blisters diffusely across the forearms, hands, neck, and lower legs.


A defect in which of the following steps of the heme biosynthesis pathway is most likely responsible for this patient’s symptoms?


18 year old Christopher is brought to the emergency room by his best friend Paul after suddenly getting abdominal cramps at a party. Cristopher goes to the restroom while you ask Paul a few questions. Paul tells you that Cristopher was behaving strangely at the party, and adds that it was his first time drinking alcohol. When Christopher comes back from the restroom, he tells you that his urine had a reddish color. Unfortunately, his family history is unknown, since he was adopted at a very young age. Next to him, there’s 45 year old Magdalene, who developed skin blisters on her hands and forearms after spending the day having some alcoholic cocktails on the beach. Upon further questioning, Magdalene mentions that her urine had a strange tea color earlier. You decide to take a look at her past medical history, which reveals that Magdalene had hepatitis C a few weeks ago.

Based on the initial presentation, both Christopher and Magdalene seem to have some form of heme synthesis disorder. Heme synthesis disorders are associated with hereditary or acquired deficiencies of enzymes that are involved in the heme synthesis pathway. But first let’s go over the heme synthesis pathway really quick! It’s important to remember that heme synthesis occurs in the liver, where heme is used in the cytochrome P450 enzyme system, as well as in the bone marrow where heme is used to synthesize hemoglobin. Now, heme synthesis begins in the mitochondria, where succinyl CoA binds to glycine via aminolevulinic acid or ALA synthase to produce aminolevulinic acid or ALA. Remember, this is the rate-limiting step for heme synthesis, meaning that it’s the slowest step in the pathway, and it requires vitamin B6, or pyridoxine, as a cofactor. What’s also high yield is that this step is stimulated by low levels of heme, while it’s inhibited by elevated levels of heme, as well as glucose and hemin, which is an oxidized form of heme that contains ferric iron or Fe3+ with chloride. Okay, then, ALA is transported to the cytosol, where it gets converted to porphobilinogen or PBG via aminolevulinic acid or ALA dehydratase, which is a zinc-containing enzyme. From there, four molecules of porphobilinogen come 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 via uroporphyrinogen III cosynthase to uroporphyrinogen III, which is then turned to coproporphyrinogen III via uroporphyrinogen decarboxylase Next, coproporphyrinogen III is brought back into the mitochondria and converted into protoporphyrinogen IX, which is then converted to protoporphyrin IX. Lastly, the enzyme ferrochelatase adds an iron molecule to protoporphyrin IX, and we’ve got ourselves a complete molecule of heme!


  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Hemoglobin: Emerging marker in stable coronary artery disease" Chronicles of Young Scientists (2011)

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