A 28-year-old woman comes to the emergency department with acute-onset abdominal pain, nausea, and confusion. She has no significant past medical history and does not use tobacco or alcohol as they have made her feel sick in the past. Serum lipase and liver function tests are within normal limits. CT scan of the abdomen shows no abnormalities. A sample of her urine is reddish in color and darkens on standing for 24 hours. Intravenous dextrose is administered and her symptoms improve significantly. Dextrose infusion most likely improved this patient's condition by affecting which of the following pathways?
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This patient most likely has acute intermittent porphyria (AIP), an autosomal dominant disorder of the heme synthesis pathway caused by porphobilinogen (PBG) deaminase deficiency. In general, enzyme deficiencies in the early steps of porphyrin synthesis cause neurovisceral symptoms (acute porphyrias); deficiencies in the latter steps (after condensation of PBG to HMB) result in photosensitivity (cutaneous porphyrias).
AIP is an acute porphyria that causes nervous system dysfunction due to the accumulation of early heme pathway intermediates (PBG and delta-aminolevulinic acid [ALA]). It presents acutely with variable gastrointestinal and neurologic symptoms, most commonly abdominal pain, vomiting, peripheral neuropathy, and neuropsychiatric derangements. A key feature of acute porphyrias is reddish urine that darkens on exposure to light and air due to the oxidation of excess PBG.
Treatment and prevention of acute porphyria attacks is directed at inhibiting ALA synthase (the rate-limiting enzyme of heme synthesis) to reduce formation of the toxic intermediate metabolites. ALA synthase is upregulated by CYP450 inducers (eg, most antiepileptics, griseofulvin, rifampin) and downregulated by heme and glucose. As such, avoidance of alcohol, smoking, and other CYP450-inducing drugs is important for preventing acute attacks. Likewise, intravenous heme administration and carbohydrate loading (such as with dextrose infusion) are useful for ameliorating acute symptoms.
(Choices A, B, C, E, and F) Administration of intravenous dextrose inhibits peroxisome proliferator-activated receptor-gamma, a transcription factor that induces synthesis of ALA synthase. This improves the symptoms of AIP by reducing the overall activity of the porphyrin synthesis pathway.
Educational objective:
Acute intermittent porphyria is an autosomal dominant condition caused by porphobilinogen deaminase deficiency. Most patients remain asymptomatic, but a minority present with acute attacks characterized by abdominal pain and vomiting, peripheral neuropathy, neuropsychological symptoms, and reddish-brown urine. Treatment consists of intravenous glucose or heme preparations, which downregulate ALA synthase activity.