A 39-year-old woman comes to the emergency department due to several episodes of severe upper abdominal pain. Her pain is triggered by fatty foods and resolves spontaneously. The symptoms first began a few months earlier after an uncomplicated pregnancy. Past medical history is notable for hypertension, for which the patient takes a calcium channel blocker, and hypertriglyceridemia, which is treated with a fibrate. Temperature is 37.2 C (98.9 F) and blood pressure is 143/76 mm Hg. The patient weighs 95 kg (210 lb) and is 173 cm (5 ft 8 in) tall. Ultrasound reveals thickening of the gallbladder wall, with tenderness elicited by the ultrasound probe directly over the gallbladder. She undergoes a laparoscopic cholecystectomy, with multiple stones noted in the contents of the gallbladder. Decreased activity of which of the following enzymes would most likely have contributed to this patient's condition?

Question

A 39-year-old woman comes to the emergency department due to several episodes of severe upper abdominal pain.  Her pain is triggered by fatty foods and resolves spontaneously.  The symptoms first began a few months earlier after an uncomplicated pregnancy.  Past medical history is notable for hypertension, for which the patient takes a calcium channel blocker, and hypertriglyceridemia, which is treated with a fibrate.  Temperature is 37.2 C (98.9 F) and blood pressure is 143/76 mm Hg.  The patient weighs 95 kg (210 lb) and is 173 cm (5 ft 8 in) tall.  Ultrasound reveals thickening of the gallbladder wall, with tenderness elicited by the ultrasound probe directly over the gallbladder.  She undergoes a laparoscopic cholecystectomy, with multiple stones noted in the contents of the gallbladder.  Decreased activity of which of the following enzymes would most likely have contributed to this patient's condition?

Quizplus · Accepted Answer

11ec160b_36d2_0f54_9249_fb3072f329ca_MD0001_00 This patient, with recurring abdominal pain, a positive "sonographic Murphy sign," and multiple cholesterol gallstones, has acute cholecystitis. Water-insoluble cholesterol is secreted in bile, where it is solubilized by detergent-like bile salts and phosphatidylcholine. If there is more cholesterol than can be dissolved by the bile salts, it will precipitate into insoluble crystals, leading to formation of gallstones. Risk factors for gallstone formation include obesity or rapid weight loss, female sex, glucose intolerance, and hypomotility of the gallbladder (eg, pregnancy, prolonged fasting). Fibrate medications (eg, fenofibrate, gemfibrozil) upregulate lipoprotein lipase, resulting in increased oxidation of fatty acids. In addition, fibrates inhibit cholesterol 7α-hydroxylase, which catalyzes the rate-limiting step in the synthesis of bile acids. The reduced bile acid production results in decreased cholesterol solubility in bile and favors the formation of cholesterol stones. (Choice A) Estrogens increase the biosynthesis of cholesterol by upregulating hepatic HMG-CoA reductase activity. Estrogenic medications (eg, estrogen replacement therapy, combined oral contraceptives) increase the amount of cholesterol secreted in bile and contribute to formation of gallstones. Aromatase catalyzes the conversion of androgens to estrogen; inhibition would lead to reduced gallstone formation. (Choice B) β-glucuronidase is released by damaged hepatocytes and bacteria in infected bile. It deconjugates bilirubin, and the resulting free bilirubin precipitates with calcium in the bile to form pigmented gallstones. Decreased activity of this enzyme would reduce the formation of pigmented stones but would not affect the formation of cholesterol gallstones. (Choices D and E) The first step in cholesterol synthesis is the condensation of 2 molecules of acetyl-CoA by acetyl-CoA acetyl transferase (thiolase) to form acetoacetyl-CoA. Condensation with a third molecule of acetyl-CoA yields β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). HMG-CoA reductase then catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol synthesis. Decreased activity of these enzymes would reduce cholesterol synthesis and the amount of cholesterol secreted in bile, discouraging cholesterol stone formation. Educational objective: Fibrate medications (eg, fenofibrate, gemfibrozil) inhibit cholesterol 7α-hydroxylase, which catalyzes the rate-limiting step in the synthesis of bile acids. The reduced bile acid production results in decreased cholesterol solubility in bile and favors the formation of cholesterol gallstones. __________ References: Safety considerations with fibrate therapy. (http://www.ncbi.nlm.nih.gov/pubmed/17368275)

A 39-Year-Old Woman Comes to the Emergency Department Due to Several