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Carbohydrate Intake: A Risk Factor for Biliary Sludge and Stones During Pregnancy Alan C. Wong, MD, MPH Cynthia W. Ko, MD, MS Department of Medicine Division.

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Presentation on theme: "Carbohydrate Intake: A Risk Factor for Biliary Sludge and Stones During Pregnancy Alan C. Wong, MD, MPH Cynthia W. Ko, MD, MS Department of Medicine Division."— Presentation transcript:

1 Carbohydrate Intake: A Risk Factor for Biliary Sludge and Stones During Pregnancy Alan C. Wong, MD, MPH Cynthia W. Ko, MD, MS Department of Medicine Division of Gastroenterology Seattle, Washington

2 Introduction Gallstone disease results in >700,000 cholecystectomies each year. Female gender is a risk factor, and pregnancy is a high risk period for gallstone formation. Gallbladder (GB) disease is the most common non- obstetrical cause of maternal rehospitalization in the first 60 days after delivery. Carbohydrate intake has been linked to increased risk of cholecystectomy in women. The effect of carbohydrate consumption on GB disease during pregnancy is unclear.

3 Study Aim To determine the effect of dietary carbohydrate intake on the formation of biliary sludge and stones during pregnancy.

4 -Prospective study -Cohort of pregnant women -Exposure: Carbohydrate consumption during pregnancy, determined by food frequency questionnaire. -Outcome: Formation of new GB sludge/stones, determined by serial GB ultrasound. Study Design – General Overview

5 Consecutive women attending 1 st obstetrics clinic (n = 8,929) Eligible and interested (n = 4,897) Gallstones on entry GB ultrasound (n = 208) Had cholecystectomy (n = 33) Did not complete dietary questionnaire (n = 184) Fewer than two GB ultrasounds (n = 1,402) Included in analysis (n = 3,070) Age 20 weeks pregnant, declined to participate (n = 4,032)

6 1 st trimester (10-12 weeks) 2 nd trimester (17-19 weeks) Post-partum (4-6 weeks) 3 rd trimester (26-28 weeks) Serial fasting gallbladder ultrasounds Definition of incident GB sludge/stones: -Progression of baseline sludge to stones or -New sludge or -New stones Minimum of 2 interpretable ultrasounds per subject

7 Ultrasonographic Definitions: 1) Sludge: low-level echoes, shift with positional changes, no post-acoustic shadowing. 2) Stones: high-amplitude echoes, >2 mm in diameter, post-acoustic shadowing present. Interpretation: -Technicians had specific training in GB ultrasound -Images reviewed by 1 of 2 radiologists

8 Measurement of Carbohydrate Intake 1 st trimester2 nd trimesterPost-partum3 rd trimester Dietary Questionnaire -Validated food frequency questionnaire -Daily consumption (g/day) of total carbohydrate, starch, sucrose, galactose, fructose, lactose, and maltose. 3 rd trimester

9 Statistical Methods -Risk of incident GB sludge/stones determined for each quartile of intake of total carbohydrate and individual carbohydrates (starch, sucrose, galactose, fructose, lactose, and maltose) -Multivariate logistic regression adjusting for: -age -pre-pregnancy body mass index -weight gain during pregnancy -parity -Hispanic origin -smoking -history of diabetes -intake of alcohol, caffeine, total calories, protein, fat, fiber, cholesterol, fatty acids

10 Results

11 Incidence of GB disease = 10.2% New sludge = 5.1% New stones = 2.8% Baseline sludge to stones = 2.3%

12 Characteristics of Study Subjects Results No new sludge/stonesNew sludge/stonesP - value n = 2756n = 314 Hispanic origin (%) BMI pre-pregnancy (kg/m 2 )2427 < Weight gain during pregnancy (kg) < Caffeine intake (mg/day) Alcohol intake (g/day) No significant difference between groups: -history of diabetes -gestational diabetes -intake of calories, fat, fiber

13 NutrientAdjusted Odds Ratio95% Confidence Interval Total carbohydrate Starch * Fructose * Galactose * Results Carbohydrate consumption and the risk of incident gallstone disease * With additional adjustment for total carbohydrate intake - A djusted for: age, pre-pregnancy BMI, weight gain, parity, Hispanic origin, smoking, history of diabetes, intake of alcohol, caffeine, calories, protein, fat, fiber, cholesterol, fatty acids - Highest quartile of intake compared to lowest quartile

14 Carbohydrate consumption and the risk of incident gallstone disease * P < 0.05, compared to Quartile 1

15 Discussion

16 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy

17 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Hyperinsulinemia + Insulin resistance

18 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Hyperinsulinemia + Insulin resistance Postprandial insulin ↑ 3-fold Basal insulin ↑ 2-fold Insulin sensitivity ↓ 50-70%

19 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Bile cholesterol super-saturation ↑ bile cholesterol saturation ↑ bile cholesterol secretion ↓ bile acid synthesis Hyperinsulinemia + Insulin resistance

20 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Bile cholesterol super-saturation GB stasis ↑ bile cholesterol saturation ↑ bile cholesterol secretion ↓ bile acid synthesis ↓ GB ejection fraction ↓ GB emptying response to CCK Hyperinsulinemia + Insulin resistance

21 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Bile cholesterol super-saturation GB stasis ↑ bile cholesterol saturation ↑ bile cholesterol secretion ↓ bile acid synthesis ↓ GB ejection fraction ↓ GB emptying response to CCK Hyperinsulinemia + Insulin resistance Carbohydrates

22 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Bile cholesterol super-saturation GB stasis Carbohydrates ↑ bile cholesterol saturation ↑ bile cholesterol secretion ↓ bile acid synthesis ↓ GB ejection fraction ↓ GB emptying response to CCK Hyperinsulinemia + Insulin resistance

23 ↑ cortisol ↑ estrogen ↑ progesterone ↑ human placental lactogen Pregnancy Bile cholesterol super-saturation GB stasis ↑ bile cholesterol saturation ↑ bile cholesterol secretion ↓ bile acid synthesis ↓ GB ejection fraction ↓ GB emptying response to CCK Hyperinsulinemia + Insulin resistance Carbohydrates

24 Fructose

25 – does not require insulin for uptake into cells – stimulates less insulin release than glucose – largely metabolized in the liver

26 Fructose leptin resistance ↑ leptin level hepatic lipogenesis ↑ triglyceride hepatic insulin resistance

27 Fructose leptin resistance ↑ leptin level hepatic lipogenesis ↑ triglyceride hepatic insulin resistance Gallstone disease

28 Limitations 1)Only one dietary time point 2)GB ultrasounds were done at varying stages of pregnancy 3)No serum insulin/leptin levels

29 High intake of total carbohydrate, starch, and fructose is associated with increased risk of developing biliary sludge/stones during pregnancy. Dietary modification during pregnancy may reduce this risk. Conclusion

30 References American Gastroenterological Association. The burden of gastrointestinal diseases. Bethesda, MD: The American Gastroenterological Association, Lydon-Rochelle M et al. Association between method of delivery and maternal rehospitalization. JAMA May 10;283(18): Tsai CJ et al. Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women. Gastroenterology Jul;129(1): Nakeeb A et al. Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg Jul- Aug;10(7):940-8; discussion Gielkens HA et al. Effect of insulin on basal and cholecystokinin-stimulated gallbladder motility in humans. J Hepatol Apr;28(4): Dubrac S et al. Insulin injections enhance cholesterol gallstone incidence by changing the biliary cholesterol saturation index and apo A-I concentration in hamsters fed a lithogenic diet. J Hepatol Nov;35(5): Biddinger SB et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med Jul;14(7): Epub 2008 Jun 29. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr May;71(5 Suppl):1256S-61S. Wang HH et al. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochim Biophys Acta Nov;1791(11): Wu Z et al. Progesterone inhibits L-type calcium currents in gallbladder smooth muscle cells. J Gastroenterol Hepatol Dec;25(12): Miller A et al. Dietary fructose and the metabolic syndrome. Curr Opin Gastroenterol Mar;24(2): Ko CW et al. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology Feb;41(2): This study is supported by National Institutes of Health (NIH) grant DK 46890

31 Thank You


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