Carbohydrate Intake: A Risk Factor for Biliary Sludge and Stones During Pregnancy

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. Study Design – General Overview • 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.

5. Consecutive women attending 1st obstetrics clinic (n = 8,929) Age <18, poor language comprehension, >20 weeks pregnant, declined to participate (n = 4,032) Eligible and interested (n = 4,897) Gallstones on entry GB ultrasound (n = 208) Had cholecystectomy (n = 33) Fewer than two GB ultrasounds (n = 1,402) Did not complete dietary questionnaire (n = 184) Included in analysis (n = 3,070)

6. Serial fasting gallbladder ultrasounds 1st trimester (10-12 weeks) 2nd trimester (17-19 weeks) 3rd trimester (26-28 weeks) Post-partum (4-6 weeks) • 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 1st trimester 2nd trimester 3rd trimester 3rd trimester Post-partum Dietary Questionnaire • Validated food frequency questionnaire • Daily consumption (g/day) of total carbohydrate, starch, sucrose, galactose, fructose, lactose, and maltose.

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. Results • 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 significant difference between groups: • history of diabetes • gestational diabetes • intake of calories, fat, fiber

13. Results • Carbohydrate consumption and the risk of incident gallstone disease • - Highest quartile of intake compared to lowest quartile • - Adjusted 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 • * With additional adjustment for total carbohydrate intake

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

15. Discussion

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

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

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

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

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

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

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

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

24. Fructose

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

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

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

28. Limitations • Only one dietary time point • GB ultrasounds were done at varying stages of pregnancy • No serum insulin/leptin levels

29. Conclusion • 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.

30. References • American Gastroenterological Association. The burden of gastrointestinal diseases. Bethesda, MD: The American Gastroenterological Association, 2001. • Lydon-Rochelle M et al. Association between method of delivery and maternal rehospitalization. JAMA. 2000 May 10;283(18):2411-6. • Tsai CJ et al. Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women. Gastroenterology. 2005 Jul;129(1):105-12. • Nakeeb A et al. Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg. 2006 Jul-Aug;10(7):940-8; discussion 948-9. • Gielkens HA et al. Effect of insulin on basal and cholecystokinin-stimulated gallbladder motility in humans. J Hepatol. 1998 Apr;28(4):595-602. • 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. 2001 Nov;35(5):550-7. • Biddinger SB et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008 Jul;14(7):778-82. Epub 2008 Jun 29. • Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J ClinNutr. 2000 May;71(5 Suppl):1256S-61S. • Wang HH et al. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. BiochimBiophysActa. 2009 Nov;1791(11):1037-47. • Wu Z et al. Progesterone inhibits L-type calcium currents in gallbladder smooth muscle cells. J GastroenterolHepatol. 2010 Dec;25(12):1838-43. • Miller A et al. Dietary fructose and the metabolic syndrome. CurrOpinGastroenterol. 2008 Mar;24(2):204-9. • Ko CW et al. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology. 2005 Feb;41(2):359-65. This study is supported by National Institutes of Health (NIH) grant DK 46890

31. Thank You