A 62-year-old man comes to the emergency department due to severe colicky upper abdominal pain, nausea, and vomiting. He reports several episodes of similar abdominal discomfort in the past. The patient does not use tobacco, alcohol, or illicit drugs. He immigrated to the United States from East Asia several years ago. Physical examination shows right upper quadrant abdominal tenderness. An imaging study shows several gallstones in the common bile duct and gallbladder. The stones are removed from the duct endoscopically, and a cholecystectomy is also performed. The gallstones are dark brown, soft, and composed primarily of calcium bilirubinate with variable amounts of cholesterol. Which of the following enzymes most likely played an important role in the pathogenesis of this patient's condition?
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Gallstones can be categorized as cholesterol, pigment, or mixed stones. Cholesterol stones are formed when the ability of bile salts to solubilize cholesterol is overwhelmed by high concentrations of cholesterol in bile. Cholesterol stones are yellow to pale gray and hard. By contrast, pigment gallstones are composed of calcium salts of unconjugated bilirubin, are comparatively soft, and are dark brown to black.
Brown pigment stones typically arise secondary to bacterial (eg, Escherichia coli) or helminthic (eg, Ascaris lumbricoides, Clonorchis sinensis) infection of the biliary tract, which results in the release of beta-glucuronidase by injured hepatocytes and bacteria. This enzyme hydrolyzes bilirubin glucuronides and increases the amount of unconjugated bilirubin. The liver fluke C sinensis is a common cause of pigmented stones in East Asian countries and can have a prolonged quiescent phase before inducing symptoms.
Pigment stones may also occur in the absence of infection when excess bilirubin is excreted, such as with chronic hemolytic anemia. A small amount of conjugated bilirubin normally becomes deconjugated by endogenous beta-glucuronidase in the biliary tract. When large amounts of conjugated bilirubin are excreted into the bile, enough becomes deconjugated to promote black pigment stone formation.
(Choice A) Inhibition of 7-alpha-hydroxylase (eg, fibrates) reduces the conversion of cholesterol to bile acids and increases the risk of cholesterol stones. However, this patient's gallstones are composed primarily of unconjugated bilirubin, not cholesterol.
(Choices B and E) Aromatase catalyzes the conversion of androgens to estrogen, which increases hepatic cholesterol uptake. In addition, estrogens upregulate HMG Co-A reductase, which increases cholesterol synthesis. This increases biliary excretion of cholesterol, favoring formation of cholesterol stones, not pigment stones.
(Choice D) Desmolase (cholesterol side-chain cleavage enzyme) catalyzes the conversion of cholesterol to pregnenolone, which is the first step in the synthesis of steroid hormones.
Educational objective:
Brown pigment gallstones are composed of calcium salts of unconjugated bilirubin and arise secondary to bacterial or helminthic infection of the biliary tract. Beta-glucuronidase released by injured hepatocytes and bacteria hydrolyzes bilirubin glucuronides to unconjugated bilirubin. The liver fluke Clonorchis sinensis has a high prevalence in East Asian countries and is a common cause of pigment stones.