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

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

Alan C. Wong, MD, MPHCynthia W. Ko, MD, MS

Department of MedicineDivision of Gastroenterology

Seattle, Washington

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.

Study Aim

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

- 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

Consecutive women attending 1st 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 <18, poor language comprehension, >20 weeks pregnant, declined to participate (n = 4,032)

1st trimester(10-12 weeks)

2nd trimester(17-19 weeks)

Post-partum(4-6 weeks)

3rd 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

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

Measurement of Carbohydrate Intake

1st trimester 2nd trimester Post-partum3rd trimester

Dietary Questionnaire

- Validated food frequency questionnaire

- Daily consumption (g/day) of total carbohydrate, starch, sucrose, galactose, fructose, lactose, and maltose.

3rd trimester

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

Results

Results

Incidence of GB disease = 10.2%

• New sludge = 5.1%

• New stones = 2.8%

• Baseline sludge to stones = 2.3%

Characteristics of Study Subjects

Results

No new sludge/stones New sludge/stones P - value

n = 2756 n = 314

Hispanic origin (%) 10.4 17.8 0.001

BMI pre-pregnancy (kg/m2) 24 27 <0.0001

Weight gain during pregnancy (kg) 14.6 12.6 <0.0001

Caffeine intake (mg/day) 40 50 0.018

Alcohol intake (g/day) 0.1 0.5 0.038

No significant difference between groups:- history of diabetes- gestational diabetes- intake of calories, fat, fiber

Nutrient Adjusted Odds Ratio 95% Confidence Interval

Total carbohydrate 2.295 1.130 - 4.661

Starch* 1.812 1.002 - 3.277

Fructose* 2.054 1.183 - 3.568

Galactose* 0.664 0.441 - 0.999

Results

Carbohydrate consumption and the risk of incident gallstone disease

* With additional adjustment for total carbohydrate intake

- 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

- Highest quartile of intake compared to lowest quartile

Quartile 1 Quartile 2 Quartile 3 Quartile 40

0.5

1

1.5

2

2.5

Total carbohydrate Starch Fructose Galactose

Odd

s Ra

tio

*

*

*

*

**

Carbohydrate consumption and the risk of incident gallstone disease

* P < 0.05, compared to Quartile 1

Discussion

↑ cortisol↑ estrogen

↑ progesterone↑ human placental lactogen

Pregnancy



Pregnancy

Hyperinsulinemia+

Insulin resistance



Pregnancy

Hyperinsulinemia+

Insulin resistance

Postprandial insulin ↑ 3-fold

Basal insulin↑ 2-fold

Insulin sensitivity↓ 50-70%



Pregnancy

Bile cholesterol super-saturation

↑ bile cholesterol saturation

↑ bile cholesterol secretion

↓ bile acid synthesis

Hyperinsulinemia+

Insulin resistance



Pregnancy


GB stasis




↓ GB ejection fraction

↓ GB emptying response to CCK

Hyperinsulinemia+

Insulin resistance



Pregnancy


GB stasis






Hyperinsulinemia+

Insulin resistance

Carbohydrates



Pregnancy


GB stasisCarbohydrates






Hyperinsulinemia+

Insulin resistance



Pregnancy


GB stasis






Hyperinsulinemia+

Insulin resistance

Carbohydrates

Fructose

Fructose

– does not require insulin for uptake into cells

– stimulates less insulin release than glucose

– largely metabolized in the liver

Fructose

leptin resistance↑ leptin level

hepatic lipogenesis↑ triglyceride

hepatic insulin resistance

Fructose

leptin resistance↑ leptin level

hepatic lipogenesis↑ triglyceride

hepatic insulin resistance

Gallstone disease

Limitations

1) Only one dietary time point

2) GB ultrasounds were done at varying stages of pregnancy

3) No serum insulin/leptin levels

• 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

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 Clin Nutr. 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. Biochim Biophys Acta. 2009 Nov;1791(11):1037-47.• Wu Z et al. Progesterone inhibits L-type calcium currents in gallbladder smooth muscle cells. J Gastroenterol

Hepatol. 2010 Dec;25(12):1838-43. • Miller A et al. Dietary fructose and the metabolic syndrome. Curr Opin Gastroenterol. 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

Thank You

Documents

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