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The Gallstone Story:Pathogenesis and Epidemiology

INTRODUCTION

Gallstone disease remains one of the most com-mon medical conditions in the United States andin developed countries in general. 14 Among bil-

iary tract disease, it is the leading cause for inpatientadmissions for gastrointestinal problems. 5,6 In theUnited States in 2000 alone, there were 262,411 hos-pitalizations for cholecystitis and 778,632 outpatientvisits. 5 The average cost per each admission was$11,584. 5 Between 19941998, an estimated 20.5 mil-lion American adults were diagnosed with cholelithia-sis,1 which equates to approximately 15% of theAmerican population. The most accurate and noninva-sive method of predicting gallstone disease was

achieved with the advent of the ultrasound, which hasa sensitivity/specificity of greater than 95%. However,the true prevalence of the disease remains hard to

derive as the majority of patients remain asympto-matic. Recent studies indicate that only 10%18% of patients with cholelithiasis develop symptoms such asnausea, vomiting and abdominal pain.

This paper will review the pathogenesis and epi-demiology of gallstone disease, focusing on both un-modifiable and modifiable risk factors.

PATHOGENESISGallstones are principally formed due to abnormal bileconstituents (eg, cholesterol, phospholipids and bilesalts). Cholesterol gallstone formation can be arbitrar-ily divided into 3 stages: cholesterol saturation, nucle-ation, and stone growth (Figure 1). 7

Cholesterol Solubilization and Super SaturationCholesterol is virtually insoluble in aqueous solutionand requires some vehicle to render it soluble in bile. 7This is overcome by secretion of phospholipids andbile salts along with cholesterol. The biliary lipids(lecithin, cholesterol, and bile salts) are secreted intothe hepatic canaliculi by adenosine tri-phosphate

DISEASES OF THE BILIARY TRACT, SERIES #4

Neil Bajwa, MD; Rajinder Bajwa, MD; AmbrishGhumman, MD; R.M. Agrawal, MD, FACG, AGAF,FASGE; Allegheny General Hospital, Drexel Univer-sity College of Medicine, Division of Gastroenterology,Pittsburgh, PA.

R. M. Agrawal, M.D., Series Editor

Neil Bajwa Rajinder Bajwa Ambrish Ghumman R. M. Agrawal

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PRACTICAL GASTROENTEROLOGY SEPTEMBER 201012


The Gallstone Story

(ATP)-dependent transport proteins. 4 Soon after theexcretion, cholesterol and lecithin combine to formmetastable unilamellar vesicles, while the bile salts,after reaching a critical concentration, form simplemicelles. The dynamic interaction of unilamellar vesi-cles with the simple micelles leads to the formation of mixed micelles during the passage through the biliarytract into the gallbladder. 8,9 Studies have shown thatvesicles are able to solublize more cholesterol thanmixed micelles. The concentration of phospholipidsand bile salts relative to cholesterol is thought to be thecritical factor in determining the solublization and sat-uration of cholesterol in bile and thus making it morelithogenic if homeostasis is not maintained.

Nucleation of Cholesterol CrystalsNucleation is the process by which cholesterol monohy-drate crystals form and agglomerate. 7 In supersaturatedbile, the interaction between mixed micelles and vesi-cles lead to precipitation of cholesterol crystals. Video

enhanced microspic studies have shown that crystalsappeared to originate from aggregated vesicles. 7,10 Thisobservation is explained by the fact that when the vesi-cles and mixed micelles interact in the gallbladder, themicelles remove phospholipids from the vesicles inpreference to cholesterol, thus making vesicles rich incholesterol. 7 The remaining vesicles are relativelyenriched in cholesterol and prone to nucleation. Afternucleation, crystallization of the cholesterol can thenoccur eventually leading to the formation of macro-scopic gallstones. Initially super saturation was thoughtto be the primary pathological event leading to the for-mation of gallstones, however with the advent of assaysto determine the nucleation time and the observation of asymptomatic super saturation of gallstones in patients,it has become evident that nucleation of the cholesterolcrystals plays a vital role in the overall development of gallstones. Nucleation time can be decreased by certainpro-nucleation factors such as gallbladder mucin, heat-labile glycoprotein, immunoglobulin, phospholipase C,and most likely, calcium. 8 Factors which slow nucle-

Figure 1. Pathogenesis of cholesterol gallstones .

Excretion ands u persat u ration

Nu cleation

Stone gro w th

CTP: Phosphocholine

Cytidyly transferase HMG-Co A Red u ctase

Cholesterol

7 -hydroxylase

Cholesterol (CH) Bile salts (BS)Phosphatidyl choline (PC)(Lecithin)

BS simple micelles

Simple BS-CH micelles

Mixed BS-CH-PL micelles

PL-CH vesicle

CH monohydrate crystals

Cholesterol gall stones

Unilamellar PC-CH-(BS) v esicles

Mu ltilamellar PL-CH-(BS) vesicles

Fu se


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ation include apolipoprotein AI and AII and a 120-kDglycoprotein. 8

Cholesterol Stone GrowthThe nucleated cholesterol monohydrate crystal servesas the nidus for the growth of cholesterol stones. 8

Repeated deposition of cholesterol on the nidus leadsto stone enlargement. Growth of stones is most likelya discontinuous process that is punctuated by deposi-tion of rings of calcium bilirubinate and calcium car-bonate as the daily inter-play of cholesterol, bile saltsand phospholipids continues. 8

There are several factors that favor cholesterolgallstone formation. The first is cholesterol hyper-secretion, which can occur due to advanced age, obe-sity, hormones (eg, estrogens, progesterone, use of oralcontraceptive pills), medications (eg, clofibrate), andmarked weight reduction. Pro-nucleating factors(including mucus, glycoproteins, high bile salt tolecithin ratio, high cholesterol to lecithin ratio in vesi-cles, infections, calcium and bacterial biofilms) andgallbladder stasis (which can occur from total par-enteral nutrition, octreotide use, pancretic insuffi-ciency, and spinal cord injury) also increase the risk of

cholesterol gallstone formation. Finally, conditionscausing a decrease in bile acids, such as ileal disease,bypass or resection of the ileum, primary biliary cir-rhosis, congenital 12-hydroxylase deficiency, andcholestyramine can increase the chance of gallstonedisease. These factors will be discussed in detail laterin this review.

Pigment stones make up a small minority andaccount for approximately 10%30% of gallstonecases in the United States. 11,12 This review will notexplore in depth the pathogenesis of pigment gall-stones due to a lack of epidemiological studies.Briefly, there are 2 types of pigment gall stones: blackand brown gallstones. Black pigment stones are pre-dominantly composed of an insoluble bilirubin pig-ment polymer mixed with calcium phosphate andcarbonate. 13 Precipitation of calcium bilirubinateoccurs whenever the ionic product of calcium andunconjugated bilirubin exceeds its solubility product.The major factors causing black pigment stones arehemolytic anemias, ineffective erythropoiesis, and

increased production of bilirubin (caused by hereditaryspherocytosis, thalassaemia, sickle cell disease, livercirrhosis, malaria, and ineffective erythropoiesis). 13

Factors causing absorption of bilirubin from gutinclude ileal resection or ileal disease, liver cirrhosis,total parenteral nutrition, and cystic fibrosis. 13

Most of the brown pigment stones are formed inthe bile ducts as a consequence of some infection andstasis of bile flow. 13 Chemically they are calcium saltsof long chain fatty acids and cholesterol. Bacterial B-glucuronidase deconjugates bilirubin diglucuronideinto insoluble unconjugated bilirubin which precipi-tates in the bile duct. Any factor that interrupts normalbile flow predisposes to infection, and subsequently tobrown pigment stone formation as is observed withbiliary strictures, periampullary diverticulum, and Car-oli syndrome. Intrahepatic brown pigment stones areseen with infestation of bile ducts with Ascaris lum-bricoides and Clonorchis sinensis .13

EPIDEMIOLOGY AND RISK FACTORS

Unmodifiable Risk FactorsGender Generally, gallstone disease is more prevalentin females than in males (Table 1). However, the differ-ences in gallstone incidence between sexes decreases

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The Gallstone Story

Table 1.Risk Factors

Modifiable Risk Factors

Obesity Rapid weight loss Diet Alcohol abstinence Decreased physical activity Smoking Medications (ie, octreotide, ceftriaxone) Hyperlipidemia Diabetes mellitus type II

Unmodifiable Risk Factors Female Gender Age Genetics


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with advancing age. According to the Group for Epi-demiology and Prevention of Cholelithiasis (GREPCO)study, the female-to-male ratio for gallstone disease was2.9 between 30 to 39 years of age, 1.6 between 40 to 49years of age, and 1.2 between 50 to 59 years of age. 14

Female sex hormones appear to play a role, espe-cially between the ages of 20 and 30 years. 5 Anotherstudy that researched estrogen receptors and choles-terol biosynthesis found that estrogen in particularstimulated the HMG-Co-A reductase enzyme causingincreased synthesis of cholesterol and thus puttingwomen at an increased risk of super saturation. Furthersupporting the link between estrogen and gallstones, it

was determined that postmenopausal women on estro-gen replacement therapy were found to have anincreased incidence of gallstones. 15 Progesterone mayalso contribute to gallstone disease by inhibiting gall-bladder contraction and promoting hypomotility andgallbladder stasis.

Parity also appears to be a factor in the develop-ment of gallstones. Women with more pregnancies andlonger lengths of fertility periods appear to have ahigher likelihood of developing gallstones than thosewho remain nulliparous. A study in Chile found gall-stones in 12.2% of multiparous women versus 1.3% of

nulliparous women within the same age. 16 Anotherstudy found women under the age of 25 years with 4pregnancies were 4 to 12 times more likely to developcholesterol stones compared to nulliparous women of the same age and weight. It should be noted that biliarysludge usually disappears a few weeks after the preg-nancy concludes/terminates/ends.

Age Age also appears to have an effect on the inci-dence of gallstone disease. Gallstone disease before 20years of age is a rare occurrence. 5 In infants and chil-dren, the most common stones are pigment stones,

which are related to hemolysis or chronic diseases suchas cystic fibrosis, thalassemia major, and sickle cell ane-mia.5 Typically, only 0.15% to 0.22% of children willhave gallstones, and children account for less than 5%of all cholecystectomies. The increased incidence of gallstones with age is seen across all ethnic groups. 5,17

A study in Taiwan confirmed that increasing age had adirect relationship with the development of gallstonessimply due to the long-term exposure to other risk fac-

tors irrespective of locality or standard of living. 17 ADanish study also showed that an increased incidence of

gallstone disease in patients 45 years compared withthose aged 35 years, while the differences in gallstoneincidence between sexes decreased with advancingage.18 From a biochemical standpoint, age itself mayincrease cholesterol saturation of bile with enhancedhepatic secretion of cholesterol secondary to increasedlevels of HMG co-A reductase, the rate-limiting enzymeof cholesterol synthesis. Decreased synthesis of bileacids may occur secondary to decreased cholesterol7 a-hydroxylase enzyme activity, the rate-limitingenzyme in bile acid synthesis, as age advances. 19,20

Genetics It remains to be determined the exact roleof genetics in the occurrence of gallstones that wouldaccount for the different prevalence rates among thedifferent ethnic groups. However, genetic make-upappears to contribute to the prevalence of cholelithia-sis as there is wide variation in incidence between dif-ferent ethnicities (Table 2). 1,2124 For example, thePima tribe of Arizona has the highest prevalence of


The Gallstone Story

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Table 2.

Worldwide Prevalence 1,2124

Prevalence (%)

AmericasPima Indians (Arizona) 73 (women >25 years)

90 (women >65 years)Mupache Indians (Chile) 49 (women); 13 (men)

EuropeNorway 21Former East Germany 19France 14

England 8Africa

Bantu Tribe 5

AsiaNorthern India 6China 4Japan 3


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gallstone disease in the world, where an estimated73% of women >25 years have cholelithiasis, with theprevalence rising to 90% by 65 years. 21 In SouthAmerica, the prevalence of gallbladder disease amongMapuche Indians of Chile is 49% in women and 13%in men. 22 In the United States, the NHANES III surveyshowed a higher prevalence of gallstones in Mexican-Americans compared to non-Hispanic whites, whileAmerican blacks had the lowest prevalence. 1 InEurope, the highest prevalence of gallstone diseasewas found in Norway (21%) and the former East Ger-many (19%), while the lowest incidence was found inItaly (6%). 23 In Asian countries, the prevalence of cho-

lesterol gallstones is relatively low. These countriesand populations are being more commonly associatedwith pigment stones. In northern India, for example,the prevalence of cholelithiasis is about 6%. 24 How-ever, with the increased expansion of the Western dietthroughout the world, the number of stones attributedto cholesterol is expected to increase.

In individuals, studies have shown that geneticfactors are responsible for at least 30% of symptomaticgallstone disease. 2527 It has been found that monozy-gotic twins have been shown to have a higher choles-terol saturation index than dizygotic twins. 28

Furthermore, a study in Europe found linked a muta-tion in the ABCG8-gene with the occurrence of gall-stones as this mutation was carried in 21% of 178 menand women with gallstones. 29 It was found that thismutated gene was responsible for the pump whichtransported blood lipid cholesterol from the liver intothe bile ducts, therefore, increasing the formation of cholesterol gallstones.

Modifiable Risk FactorsObesity Obesity is an important risk factor for thedevelopment of gallstone disease. Obese women,defined as a body mass index (BMI) >30 kg/m 2 are attwice the risk of gallbladder disease than women witha normal BMI (40 kg/m 2 have a 7-fold increasedrisk of gallstones. 5,31 The reason for the increased riskof gallstones in obese patients is due to an increasedhepatic secretion of cholesterol. 5,32 Additionally, thecorrelation between gallstone disease and obesity is

greater with those patients with central obesity andthose who developed obesity at an early age ratherthan in the later years of life. 5,31

Rapid Weight Loss Rapid weight loss is another riskfactor for gallbladder disease, 5 as demonstrated by theNurses Health Study, 33 which followed close to 90,000women. This study found that women who lost 4 kg to10 kg of weight over a 2-year interval had a 44%increase in the risk for gallstone disease as comparedwith women whose weight changed 10kg of weight had a 94% increase in the risk for gall-stone disease as compared with women whose weightchange was 1.5 kg/week led to a dramaticincrease in the risk of gallstone formation. 34 It has alsobeen shown that sludge and gallstones develop in25%35% of extremely obese patients with weightloss secondary to bariatric surgery, usually during thefirst 6 weeks following surgery when weight loss ismost profound. 35,36

Diet and Activity Closely related to obesity andrapid weight loss are diet and physical activity. Diets

that encompass Vitamin C, moderate alcohol intake,coffee, and nut consumption lower the incidence of gallstone disease (Table 3). 5 Conversely, increasedcholesterol intake and low fiber diet, typical of West-ern diets, are predisposing risk factors for the develop-ment of gallstone disease. 5 This is best exemplified bya study, conducted in Japan after World War II and the

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The Gallstone Story

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Table 3.Diet5

Increases Risk of Gallstones

High cholesterol/ Low fiber (western diet) Total parenteral nutrition

Lowers Risk of Gallstones

Vitamin C Moderate alcohol intake Coffee Nut consumption


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ensuing Westernization of the Japanese diet. Thatstudy found that the prevalence of gallstones doubledin Tokyo after the late 1940s with a correspondingincrease in pigment-to-cholesterol gallstones. 37 Simi-lar increases in gallstone disease have also been seenin other countries, such as Saudi Arabia, where theWestern diet has become more widespread. 38

Total parenteral nutrition (TPN) also increases therisk of gallstone occurrence as demonstrated by astudy that found that the incidence of cholelithiasiswas 6.2%, 21.2%, and 38.7% at 6, 12, and 24 monthsof receiving TPN, respectively. 39

With regard to physical activity, decreased activity

increases the risk of gallstones, while many forms of activity, including vigorous or brisk walking, protectagainst gallstone disease. 40,41

Smoking, Medications, Hperlipidemia, Diabetes Mellitus II There also appears to be a very weakrelationship between gallstones and other commonmedical conditions such as chronic obstructive pul-monary disease (COPD) and coronary artery disease(CAD). Paradoxically, hyperlipidemia is only tenu-ously linked to gallstones. Although low levels of high-density lipoprotein (HDL) cholesterol and hightriglycerides are associated with gallstone disease, 42

the extent to how much the risk is increased has notclearly been defined by any major study. Other dis-eases such as diabetes mellitus seem to facilitate thedevelopment of gallstone formation secondary toincreased triglyceride levels associated obesity as wellas promoting gallbladder hypomotility and stasis. Astudy in Japan showed a moderate increase in the riskof gallstones in patients with diabetes mellitus; 43 how-ever, there is no conclusive link between these twoconditions. Smoking is even less convincingly linkedto increased risk of gallstone disease.

A multitude of various medications have beenlinked to the development of gallstones. These includethiazides, oral contraceptives, and ceftriaxone. Somato-statin is also associated with gallstone developmentbecause of its effect on impaired gallbladder emptying.

CONCLUSIONIn summary, gallstone disease is common amongdeveloped countries. Approximately 15% of Ameri-

cans display symptoms and an even greater numberremain asymptomatic, thereby making the true preva-lence difficult to determine. The underlying pathogen-esis appears to be the interaction between cholesterol,phospholipids, and bile salts and the other factorswhich promote lithogenic bile. It is important toremember that both super saturation of cholesterol inbile and nucleation of cholesterol crystals are neededfor the formation of macroscopic gallstones. Risk fac-tors for gallstones which are unmodifiable includefemale gender through increased estrogen, cholesterolsynthesis, age, and genetics. Other risk factors includeobesity, rapid weight loss, parity, and diet. Protective

factors include vitamin C intake, moderate alcoholintake, coffee, nut consumption, and exercise.

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