A 22-year-old woman comes to the hospital due to a 5-day history of nausea, constipation, and severe, poorly localized abdominal pain. She also reports anxiety, difficulty concentrating, poor sleep quality, and tingling of the limbs. The patient has had several similar episodes in the past. She does not take any medications or use tobacco, alcohol, or illicit drugs. The patient has been restricting her diet to lose weight. On examination, the abdomen is soft, nontender, and nondistended. Bowel sounds are decreased. The patient receives an intravenous infusion of a heme preparation that leads to rapid resolution of her symptoms. The improvement in symptoms is most likely due to treatment-induced downregulation of which of the following enzymes?

Question

A 22-year-old woman comes to the hospital due to a 5-day history of nausea, constipation, and severe, poorly localized abdominal pain.  She also reports anxiety, difficulty concentrating, poor sleep quality, and tingling of the limbs.  The patient has had several similar episodes in the past.  She does not take any medications or use tobacco, alcohol, or illicit drugs.  The patient has been restricting her diet to lose weight.  On examination, the abdomen is soft, nontender, and nondistended.  Bowel sounds are decreased.  The patient receives an intravenous infusion of a heme preparation that leads to rapid resolution of her symptoms.  The improvement in symptoms is most likely due to treatment-induced downregulation of which of the following enzymes?

Quizplus · Accepted Answer

11ec160b_36e3_4d7c_9249_2750c6724c35_MD0001_00 This patient with neurologic symptoms (eg, tingling, difficulty concentrating) and recurrent episodes of nonspecific abdominal pain likely has acute intermittent porphyria (AIP), an autosomal dominant disease characterized by porphobilinogen (PBG) deaminase deficiency. Management of AIP attacks includes infusion of hemin, which downregulates hepatic aminolevulinate (ALA) synthase (rate-limiting enzyme in hepatic pathway of heme synthesis). Heme, a porphyrin, is synthesized in the liver for use in the cytochrome p450 enzyme system and in the bone marrow for hemoglobin use (these 2 synthesis pathways are regulated differently). A deficiency in any of the enzymes responsible for porphyrin synthesis can result in porphyria. Clinical manifestations result from the accumulation of porphyrin precursors in blood, tissues, and urine. AIP attacks, which are characterized by acute abdominal pain and neurologic symptoms, are due to accumulation of ALA and PBG, generally resulting from a combination of 2 factors: Glucose or hemin inhibit ALA synthase and are used in AIP management. PBG deaminase deficiency by itself is generally not sufficient for development of AIP attacks (many patients with PBG deaminase deficiency are asymptomatic), and PBG deaminase enzyme activity is not directly affected by hemin infusion (Choice E). (Choices A and D) Deficiencies of ALA dehydratase and ferrochelatase (inhibited by lead) are seen with lead poisoning. Ferrochelatase deficiency is also seen with erythropoietic protoporphyria, characterized by cutaneous photosensitivity beginning in early childhood. (Choice C) Bilirubin glucuronyl transferase is a hepatic enzyme that is responsible for the conjugation of bilirubin (byproduct of heme catabolism) with glucuronide, a polar molecule that improves bilirubin solubility for subsequent biliary excretion. A decrease in glucuronyl transferase activity results in unconjugated hyperbilirubinemia. Educational objective: Acute intermittent porphyria attacks are due to the accumulation of aminolevulinate (ALA) and porphobilinogen (PBG), resulting from inherited PBG deaminase deficiency combined with ALA synthase induction (typically due to certain medications, alcohol use, or a low-calorie diet). Management with glucose or hemin inhibits ALA synthase activity.

A 22-Year-Old Woman Comes to the Hospital Due to a 5-Day