SEMINARS IN LIVER DISEASE-VOL.
10, NO. 3, 1990
Epidemiology and Natural History of Gallstone Disease
Gallstone disease is a major public health problem in the Western world from both a medical and a financial perspective. In the United States more than half a million cholecystectomies were performed in 1987,' and direct costs related to gallbladder disease can be roughly estimated at $3 billion annually. In Europe, more than 25,000 women undergo cholecystectomy per year in England and Wales,' and recent population studies in Denmark and Italy have shown that gallstone disease is detected in more than 10% of the adult population.;'-" Because reliable epidemiologic studies can provide important information regarding etiology, risk factors, natural history, and, it is hoped, prevention of diseases, many clinicians in the last decade have focused their attention on the epidemiology of gallstones. Two additional facts have further supported this renewed interest in gallstones: the spread of ultrasonography techniques, which have led to the discovery of increasing proportions of asymptomatic gallstone cases and the availability of new therapeutic nonsurgical approaches, such as litholitic bile acids, local solvents, and lithotripsy. Historically, Morgagni,' in the 18th century, from his autopsy studies on gallstone patients, observed that the prevalence of gallstone disease increased with age, advanced the hypothesis that obesity could be a risk factor for gallstones and stated some 200 years ago, that gallstones can remain asymptomatic for a whole life time. All these observations have been confirmed by recent epidemiologic studies.
EPIDEMIOLOGY OF GALLSTONES Prevalence and Incidence There is convincing evidence that the prevalence of gallstone disease is on the increase. At present, most of the data on the prevalence of the disease are still based
From tho 1,stiruro di Clinic.tr Mrdic.tr r Grr.strorrr~~rologitr. Urli\~crsirirdi Rologr~cr,Itcrly: Dil~trrtimer~to di Orlc~ologitrSl~erirnrnrtrlr r Clirlic.tr. Ftrc.oltti di Mc,dicincr r Chirurgitr di Catrrr~:trro. Urltrc,r.\itti di Keggio Calahritr. Ittrly, crnd Isrituro Slcprriorc, di Snnitir Romcr, Ituly.
Reprint requests: Dr. Sama, Istituto di Clinica Medica e Gastroenterologia. v. Massarenti 9 40138 Bologna, Italy.
on autopsy studies. Although data from autopsy studies should be interpreted with caution, since reasons for autopsy may be related to the risk of gallstone disease and may therefore over- or underrepresent the true frequency of the disease in the population, these studies had the great merit of indicating racial and geographic differences in the prevalence of gallstones. Prevalence seems to be higher in the Western world and South America, and lower in Eastern countries and Africa. '- However, compared with the last century, the prevalence of gallstones seems to be increasing not only in affluent westernized countries, but also in countries that are becoming westernized. Gallstone disease was previously rare in Eastern countries and stones were predominantly of the pigment type, but since World War 11, cholesterol-rich gallstones have become much more common and total stone prevalence has escalated. " Other studies on the prevalence of gallstones have been based on clinically diagnosed cases. Some of them derived from a selected series of patients, mainly from hospital studies.'' Hospital series, however, have the same bias as observed in autopsy studies, that is, of not being representative of the general population. Others were based on population studies of statistically valid random samples of the general population. Among the latter, the two major published studies were not primarily directed toward gallstone disease. The Framingham studyIJ investigated the prevalence and 10-year incidence of clinically diagnosed gallstones, 5,209 subjects who took part in the Heart Disease Epidemiology Study. The age at entry was 30 to 59 years. An overall prevalence of 3.9% was found, and the incidence, calculated after 10 years, was 4.5%. The Coronary Drug Project" found an overall clinical prevalence of 3.9% in an age span of 30 to 64 years. Because it is well established that a large proportion of gallstones remain asymptomatic and are therefore often ignored for many years, even until death, studies based on clinically diagnosed cases should be interpreted with caution, since they are representative of the clinical and not of the true prevalence. Realistic information on the occurrence of gallstones in a given population can derive only from systematic population-based studies, in which everyone undergoes the same diagnostic test for gallstones. In the past, the major problem has been the diagnostic test. In fact, only oral cholecystography was
''
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149
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CLAUDIA SAMA, M.D., ANTONIO MARIA MORSELLI LABATE, Ph.D., FRANCESCO TARONI, M.D., and LUlGl BARBARA, M.D.
SEMINARS IN LIVER DISEASE-VOLUME
available and therefore, because of the difficulty and expense of applying radiographic procedures in population surveys, it was used in very few studies. Sampliner et all" studied symptomatic and asymptomatic gallbladder disease in Pima Indians. They found an overall prevalence of 48.6%. This study showed a dramatic increase of gallstone prevalence in females from 12% in the 15to 24-year age group to 73% in the 25- to 34-year age group and older. Bainton and colleagues17 performed oral cholecystography on a weighted sample of the population of an industrial town in South Wales. Reported prevalence of gallstone disease was 9.2%. More recently, echography appeared, showing its fundamental role in the diagnosis of gallstone disease. Ultrasonography, besides having a high sensitivity and specificity compared with the traditional x-ray proccdures, is simple. safe, and noninvasive and therefore appears to be the better diagnostic tool for epidemiologic studies. Two Italian studies initiated the echographic era: the GREPCO".i and the Sirmione studies." The GREPCO study was based on two occupational populations of 108 1 women and 1289 men. The reported prevalence of gallstone disease in the age span 20 to 64 years was 9.4% and 8.%, respectively. The Sirmione study is a prospective study on the incidence and risk factors of gallstone disease in the town of Sirmione in the North of Italy. The first cross-sectional study on 1930 subjects aged 18 to 65 years has shown an overall prevalence of gallstone disease of I I%." In order to assess the incidence of gallstones, the population of Sirmione was again screened 5 years later. The cumulative 5 years' incidence was 3% . I " Recently, other studies reporting the prevalence of gallstone disease in general population samples assessed by ultrasonography have been co~npletedin Europe'. I". "' and in the United States." Data on prevalence of gallstone disease in Europe is shown in Table 1 . Maurer et al," comparing Hispanic populations in the United States, found the highest prevalence in Mexican Americans (23.2% in women and 7.2% in men) in comparison with Cuban Americans (15.4% in women, 4.2% in men) or Puerto Ricans (13.5% in women, 4% in men). In 1985 a Multicenter Italian Study on Epidemiology of Cholelithiasis (MICOL) was initiated in Italy. Altogether 54,000 subjects aged 30 to 69 years were TABLE 1.
Females GKEPCO' Sirmione" Sorpen\en3 Janzon et al"' Glatnbek et al'" Males
GREPCOi Sirmione" Soreensen' Glanibek et al'"
10, NUMBER 3, 1990
sampled in 18 centers from 10 different Italian regions and studied with ultrasonography." Preliminary data are now available. The mean observed prevalence was 9.5% in males and 19% in females. (unpublished observation).
Risk Factors The prevention of cholelithiasis, which is still at a very early stage, depends on a clear understanding of events concerning pathogenesis and risk factors. Although many factors have been considered in the past as well as in recent years, the current literature about epidemiology of gallstone disease makes it very difficult to support clinical observations with statistics. However, most of these factors are supported by prevalence data or clinical studies. Risk factors for pigment stones are mainly related to concomitant pathologic conditions, like hyperhemolysis due to genetic defects"." or infections, whereas risk factors for cholesterol gallstones are more related to metabolic conditions. We will now consider the major putative risk factors for gallstones, particularly with regard to those observed in the Western world, where cholesterol gallstones predominate
Both prevalence and incidence of gallstone disease increase with age. The previous observation of Morgagni7 has been confirmed by the majority of epidemiologic studies. Gallstones are very seldom found in children, and in that age group are mainly associated with hemolytic causes." When comparing several series, less than 5% of cholecystectomies are performed under the age of 20 ears.'^-'^ In Sirmione, of 135 subjects between 18 and 21 years of age, stones were detected in only one subject. The Framingham Study'" has shown that both prevalence and incidence of gallstone disease increased with age. In this study the majority of persons with gallstone disease were diagnosed during the sixth and seventh decades of life. In a study conducted in a South Wales population, Bainton and colleagues,'' on the contrary, failed to find a positive correlation between gallstones and age.
Prevalence of Gallstone Disease Assessed by Ultrasonography in Europe
ltaly ltaly Denmark Sweden Norway ltaly ltaly Denmark Norway
'@Agespan: 60-64 years. 'IAge span: 18-29 and 50-65 years. $Age: 4 8 and 53 years.
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15 0
This is probably due to the fact that the age span considered in this study (45 to 69 years) was not wide enough to allow sufficient distribution of subjects in different age groups. In recent years, both the GREPCO and the Sirmione studies,'-" as well as all studies conducted in the echographic era,3.?0.3 showed that the prevalence of gallstones increased steadily with age in both sexes. Moreover, in the Sirmione Study'' the 5-year incidence rate was about four times higher in the age span 40 to 69 years than in younger subjects. Interestingly, the cutoff point between relatively low and high incidence rate seems to be 40 years, once again confirming the old aphorism on the major risk of gallstone disease: "female, fair, fat, and forty." This finding supports also the common wisdom that the risk of developing gallstones is really much higher in the elderly than in other age groups, which derives from extrapolation of prevalence data. Sex
Most epidemiologic studies have shown that, at least in the Western world, females have a higher frequency of gallstones than males. A female preponderance has been, in fact, observed in several studies in the past, 14.10.1?.?7 29 However. the male to female ratio seems to have changed from the early reports. which showed figures of 1:4-6, to more recent studies where the ratio ' ~ . trend ' ~ has been confirmed by the is 1:2 or l e ~ s . ' ~ .This prevalence studies in the echographic era.' " "I-" Female preponderance has been observed in all age groups. although most population studies have shown that female and male prevalence rates were more similar in the older age groups (Table 2). Female preponderance has not been observed in subjects with pigment stones. where the female to male ratio is approximately 1: 1 .27 The causes of sex-related differences in prevalence of cholesterol gallstones are not fully understood at present. Pregnancy and sex hormones could be involved by altering biliary secretion'" or gallbladder motility, or both. Genetic Factors
The importance of genetic factors in the pathogenesis of cholelithiasis, although generally recognized, is
TABLE 2. Femalelmale Ratio of Prevalence of Gallstone Disease in Different Studies
20-29
Framinghaml' South Wales1' GREPCOJ-5 Sirmione" Jorgensen'
I. I 2.6 -
*Age span 50-62 years. **Age span 45-49 years.
30-39
40-49
50-59
60-69
4.3 -
3.1 2**
2.3* 2.8
1.3
2.9 2.2 2.8
1.6 1.7 4.1
1.2 2.4 2.2
-
-
1.7
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very seldom widely discussed in the recent literature, probably due to the lack of extensive and unequivocal studies. Undoubtedly, both autopsy and population StudieSX-14.31have clearly demonstrated the existence of racial differences as far as prevalence of gallstones is concerned. Some of these differences can be explained by environmental factors. as shown by the increased prevalence observed in Japan after World War 11, which doubtless related to the westernization of the country, or by the change in prevalence after immigration into high prevalence countries. "."." However, at least two examples are consistent with the fact that a diathesis for gallstone disease exists in certain ethnic groups. The first is the strikingly high prevalence of gallstones among American Indian populations (more than 70% over the age of 50 years) which probably represents the highest prevalence detected in the world.'" The second example is a recent study on gallbladder disease conducted in Mexican-American, black and white women from the United States. Diehl et al" found that Mexican-American women had a prevalence of gallstone disease of 14.7% in comparison to 9% in white and 4.5%. in black women. These differences in prevalence are not related to age distribution. obesity, or other risk factors. It is generally believed that cholelithiasis has a higher frequency among relatives of patients. However, very few studies have attempted to confirm this hypothesis. Most studies were ~ncontrolled'"~ and although some of them have shown a familial aggregation of the disease, they are influenced by bias as indicated by Spiegel" in 19 18: "individuals with a disease tend to be more aware of family members with the same disease." If inheritance is responsible fix the concentration of cases in the families of gallstone patients, this should be particularly evident for cases detected when young. This has been shown by Hagberg et al" and Van der Linden et al.'" Unfortunately, there are very few studies on cholelithiasis in twins in the medical literature. Apart from some case report on monozygotic twins," " other studies were based only on clinically diagnosed cases," or studied twins admitted to hospital^,'^ and were not able to substain a genetic explanation for the etiology of cholelithiasis. Recently. Gilat and coworkers"" have studied prospectively the frequency of gallstones in 17 1 first-degree relatives of patients with proven gallstones, compared with 200 matched controls. All subjects were studied by oral cholecystography. Gallstones were found in 20.5% of the family group and in 9% of the control group. These differences were statistically significant after controlling for known risk factors. In the Sirmione study 303 pairs of parents-sonsldaughters have been identified among the 1930 subjects participating in the study and submitted to ultrasound examination for detecting gallstones. The children were divided into two groups according to the presence or absence of gallstone in their parents. The relative risk for gallstones was significantly higher ( R R 3.3; 95% CL = 0.97-1 1.47) in sons and daughters of parents with gallstones, controlling for age and other possible confounding factor^."^ These studies, however, need further investigation, because most of the
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ET AL
EPIDEMIOLOGY O F GALLSTONE DISEASE-SAMA.
SEMINARS IN LIVER DISEASE-VOLUME
findings can also be explained by environmental factors of cholelithiasis; family dietary habit could be a factor. However, the results of these studies, although not proving the real importance of genetic factors in gallstone disease, do not exclude it. Genetic and environmental factors are not mutually exclusive and may coexist. It is hoped that in the future the use of ultrasonography in conjunction with formal genetic family studies will give a real insight into the problem.
Obesity Many clinical and epidemiologic studies indicate that cholesterol gallstones are more common in obese subjects. In a case-control study, Scragg et alJxfound that body mass index (BMI = weightiheight'), was significantly higher in female patients with gallstone than in males. The same results were observed in most population studies. In the Framingham study" women with gallstones at entry and those who developed gallstones during the study had an average relative weight higher than gallstone-free women; these differences were not observed in men. Knowler et al,'" in the study on Pima Indians, failed to find an association between obesity and gallstones in men, but the relationship between BMI and gallstone disease was statistically significant (p < 0.05) in women. In the GREPCO, Jorgensen, and Diehl studi e s , ~ . a~significant ~ . ~ ~ positive association between BMI and the presence of gallstones was observed in women but not in men. Other population studies, based on clinical prevalencei' or ultrasonography-assessed prevalence," found that both men and women with gallstones had a higher BMI than nongallstone subjects. Moreover the Sirmione study showed that the risk of developing gallstones for currently obese subjects is higher in the lower age groups and that incidence is about three times higher in obese than in nonobese subjects.'" There are at present no clear explanations for these discrepancies. The populations studied may differ in terms of the prevalence of obesity; different investigators can use different definitions of obesity, making comparisons among studies difficult; and finally BMI may not be as good an indicator of obesity in men as in women, since the index could be the same in a subject who is really obese as in a subject who is heavily muscled. The link between obesity and cholesterol gallstones is supersaturated bile. Obesity raises the saturation of bile by increasing biliary secretion of cholesterol, the latter depending probably on a higher synthesis of cholesterol in obese subjects.
Parity Pregnancy is thought by many investigators to promote gallstone formation. Most cohort studies of clinically diagnosed gallstone^"."^'^ as well as case-control showed a positive correlation between gallstudies'" '-' stones and number of pregnancies. Two and ~' to show this corstudies on American I n d i a n ~ ' " . failed relation. Among recent studies investigating the overall prevalence of gallstones in free-living populations, a sig-
10, NUMBER 3, 1990
nificant increase in gallstone prevalence was found in women who have had multiple pregnan~ies.~.".'"oth GREPCO and Sirmione studies have also demonstrated that the increase in the relative risk due to pregnancy is higher among younger than among older women. Pregnancy could influence gallstone formation in several ways. Composition of bile may be altered adversely by hormonal changes during pregnancy." Recent studies have shown sluggish gallbladder emptying during the third trimester of pregnancy;'" this could induce gallstone formation by altering bile acid enterohepatic circulation and promoting retention of cholesterol crystals, a prerequisite for gallstone formation. In addition, rapid weight variation during and after pregnancy can influence biliary lipid secretion.
Among environmental factors that can influence gallstone formation, diet has undoubtedly a prominent role. This suggestion derives from well-known cultural and geographic differences, which show a higher prevalence of gallstone disease in developed, westernized countries, which have a relative overconsumption of calories, whereas gallstones are rare in primitive rural communities. It is well known that since World War 11, an increasing incidence of gallstone disease has been observed in Japan, with relation to change in dietary habits toward a "Western style."" Moreover, prevalence of gallstones increases in subjects moving from a low to a high frequency area.".3' Unfortunately, this suggests only that something related to the westernized diet possibly favors the development of gallstones. The putative factors are highly purified carbohydrates and animal fats, together with decreased intake of dietary fiber and vegetable fats. Several investigators have studied specific aspects of diet in order to assess dietary influences on gallstone prevalence, but there are many methodologic difficulties that limit the validity of nutritional data and that should be considered when interpreting reports on nutritional studies. Moreover, until recently, the majority of articles evaluating the relationships between gallstone and diet were based on autopsy studies or symptomatic gallstones or hospital studies. However, owing to the fact that the majority of gallstones are asymptomatic, we have no information on the dietary habits of asymptomatic patients. In the past, studies in Franceh' showed a higher caloric intake in subjects with gallstone than in controls. On the contrary, data on eating habits reported in the Framingham study" failed to reveal an association between the presence of clinically diagnosed cases of gallbladder disease and daily intake of fat, protein, and cholesterol. A slight, though not significant, trend, suggesting that persons who consumed less alcohol ran a higher risk of subsequent gallbladder disease, was observed in the Framingham study. A case-control study from Australia" showed that increased intake of simple sugars was associated with an increased risk of gallstones as well as an increased intake of energy or fat, although the two latter findings were significant only in young subjects; in both sexes, in-
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creased intake of alcohol was associated with a decreased risk of developing gallstones. Diehl and coworkers," in a population study on clinical gallstone disease in Mexican Americans and non-Hispanic whites, found that women with the highest intake of total fat and linoleic acid had a reduced risk of gallbladder disease, although an opposite trend was observed in men. In a case-control study on dietary intake, in 121 women with gallstones, Pixley et alh' found an appreciably lower frequency of gallstones among vegetarian women compared with nonvegetarian women. In the GREPCO study,"j women with gallstones showed a reduced intake of sugar, cheese, meat, and bread. In this study, women with a higher daily wine consumption showed a higher, although not significant, prevalence of gallstones than women with low or no consumption of wine. Finally in the Sirmione Study"' no difference was observed in the daily intake of energy, protein, total fat, and carbohydrates between gallstone and nongallstone subjects. A lower intake of dietary fiber was associated with a higher incidence of gallstones and a slightly higher alcohol consumption was observed in nongallstone subjects, confirming previous results. From the reported data, it appears that the relation of specific dietary constituents to gallbladder disease risk is still presumed but not proved. In analyzing studies that have considered diet as a risk factor, it is important to bear in mind the existence of methodologic problems related to the difficulty to obtain an accurate dietary history, to the relationship between the time in which the study was done and the time when gallstones have developed, and finally to the possible dietary changes in symptomatic patients. Once again, only cohort studies employing gallbladder ultrasonography will possibly elucidate the relation between diet and gallstones.
Drugs I t has been indicated that some drugs can raise the saturation of bile and hence the danger of gallstones. We will discuss below oral contraceptives and fibric acid derivatives. In the 1970s several studies showed an increased frequency of gallstone disease among women using oral contraceptives. In 1973 the Boston Collaborative Drug Surveillance Programhs published the results of a casecontrol study on gallbladder disease. They found a significant higher relative risk for gallstones (based on diagnosed cholelithiasis andlor cholecystectomy) among women 20 to 34 years old using oral contraceptives. The risk was not related to the duration of oral contraceptive use. Elevated risk for gallstone disease in users of oral contraceptives was also reported in three subsequent case-control studies.". '". h7 More recent reports, derived from prospective cohort studies failed to confirm the association between oral contraceptives and cholelithiasis,3J.ss.sh If we look at the studies published in the last 5 years, results are still conflicting. A case-control study by Scragg et als4 found that use of oral contraceptives
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was associated with an increased risk of developing gallstones among young subjects but with a decreased risk among older subjects. Both GREPCO and Sirmione studies,'.' on 1081 and 1047 women, respectively, who were evaluated by ultrasonography, found no difference in frequency of gallstone disease in women who ever used and in those who never used estroprogestinic drugs. Finally, from a cross-sectional study of gallstone disease ascertained by ultrasonography in a Danish population, Jorgensen5' reported that use of oral contraceptives was significantly associated with gallstone disease in univariate analysis and that the risk was higher in older than in younger women. A possible association between gallstone and oral contraceptives has a biologic basis. In fact oral contraceptives can increase cholesterol secretion, decrease bile acid secretion, and impair gallbladder emptying," although other authors have not confirmed these findi n g ~There . ~ ~ is no clear explanation for the conflicting results reported in epidemiologic studies. Many studies have shown an increased risk of gallstones in young women, and the Royal College of General Practitioners StudyShhas shown an increased risk only for the first few years after the patients began taking the pill. They showed also a doubling of the risk when 100 or 150 p g estrogen preparations were used compared with 50 p g preparations. Ascertainment bias is also possible in studies based on clinical prevalence because of the increased medical suspicion related to the previously published reports of this association or because women taking pills are submitted to more frequent medical check-up for routine follow-up, leading to an increased probability of diagnosis. Moreover, results from cohort studies on clinically diagnosed gallstones may very well be inaccurate, since more than half of all subjects harboring gallstones are unaware of it and are therefore considered nongallstone cases. Only prospective studies investigating the incidence of gallstones on large cohorts of women of different ages and using different dosages of drugs will answer the question regarding the effect of estroprogestinic drugs in gallstone disease. Clofibrate and related drugs, which have been used for the control of hyperlipidemia, enhance the saturation of bile by increasing biliary secretion of cholesterol and decreasing synthesis of bile acid^.^" This effect has been confirmed by several epidemiologic studies, which have clearly shown an increased risk of gallstone disease in subjects using clofibrate to lower serum lipid level^.^'."
Other Diseases as Risk Factors Diabetes Autopsy studies indicate that prevalence of gallstone disease is slightly increased in diabetic s ~ b j e c t s . ~ ' - ~ ~ Epidemiologic studies conducted in vivo have, however, given conflicting results. A case-control study in Newfoundland compared the prevalence of known diabetes in 775 subjects of both sexes undergoing cholecystectomy for cholesterol cholelithiasis with 1308 agematched controls undergoing other surgical procedure^.^'
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EPIDEMIOLOGY O F GALLSTONE DISEASE-SAMA,
In this study an inverse relationship, not statistically significant, was found between diabetes and cholelithiasis. Sampliner in the earlier Pima Indian studyLhfound no association between diabetes and gallstones. whereas in the same population, Knowler et alJ" provided later evidence for a relationship of diagnosed gallstone disease, not only with diabetes but also with impaired glucose tolerance. Also Diehl et al" reported that diabetic Mexican-American, black and white females had a higher prevalence of gallstone disease than subjects without diabetes, controlling for other possible risk factors as age and obesity. In contrast, the two Italian studies, GREPCO and Sirmione,'-" and the Danish studyXVailed to observe an association between diabetes and gallstones. Differences observed in differential studies can be related perhaps to methodologic problems. In fact, the diagnostic criteria for diabetes are widely different in different studies. Some studies are based only on known diabetes; others, like the Pima study, have also used a glucose tolerance test. Both in GREPCO and Sirmione studies sub-jects with a known history of diabetes or with fasting blood glucose levels higher than 140 mgldl were defined as diabetic. A second problem concerns the diagnosis of gallstone disease. In the majority of published studies gallstone cases were clinically diagnosed, which very often are not representative of the true prevalence of the disease.
10. NUMBER 3, 1990
show an increased frequency of gallstones; however, an association between hypertriglyceridemia and gallstone disease has been observed in both sexes. The mechanisms underlying the raised plasma triglyceride levels in gallstone pati& are not fully elucidated, although the observation that patients with types IIb and IV hyperlipoproteinemia, who have an increased prevalence of gallstones, have an increased triglyceride synthesisx"and an increased hepatic cholesterol synthesis," suggests that this could be the explanation in gallstone patients. Also, the inverse association between plasma total and HDL cholesterol is not easily explained. o n e possible explanation derived from studies in ratsx'-" is that a lowered ~ l a s m atotal and HDL cholesterol could result in increascd cholesterol synthesis by the liver because high levels induce an inhibition of the synthesis itself. Another possible explanation for the inverse relationship between HDL levels and gallstones is that free cholesterol in HDL is preferentially metabolized to bile acids."
Ileal Diseases Cholelithiasis has been associated with terminal ileal diseases. Both clinical seriesx'."'and case-control studies" confirmed the association. The biologic explanation for this association is that patients with ileal disease and ileal resection have an increased loss of bile salts in the feces and diminished bile acid pool size.
Hyperlipidemia Hemolytic Anemias Bile saturated with cholesterol is recognized as a precursor to cholesterol gallstone formation. Several investigators have therefore analyzed serum lipid levels in order to try to elucidate the possible changes in lipid metabolism associated with the formation of gallstones. Ahlberg et aI7' compared serum triglyceride and serum cholesterol levels in 457 gallstone patients with those of 230 control patients. No association was found between serum cholesterol levels and gallstone disease, while gallstone patients older than 40 years had higher serum triglyceride levels than did controls. The presence of gallstone disease is also positively associated with type IV77.78and type IIb7' hyperlipoproteinemia, both of which are characterized by an increase in concentration of triglyceride-rich very low density lipoproteins. In a cross-sectional study of patients with gallstone disease, Petitti et a17' reported an inverse relationship between gallbladder disease and HDL levels. A recent case-control study by Scragg et a17" confirmed these results. They found, using a multivariate method of analysis, that increased triglyceride concentrations were associated with an increased risk of gallstones in young subjects only; they found also that increased plasma total and high density lipoprotein (HDL) cholesterol concentrations were associated with a decreased risk of gallstones. In the GREPCO study,' using a multiple logistic regression analysis, a positive correlation was found between presence of gallstones and high serum triglyceride levels and with decreasing total (and low density lipoprotein) cholesterol. Also in the Sirmione study,' hypercholesterolemic subjects did not
He~nolyticanemias are associated with gallstone disease of the pigment type."-'" The possible explanation is probably an increased production and biliary secretion of bilirubin, which can induce gallstone formation.
NATURAL HISTORY OF GALLSTONE DISEASE Studies on the natural history of gallstones have received considerable attention in recent years, owing to the fact that: ( I ) the widespread use of ultrasonography results in asymptomatic gallstones being identified more frequently as "incidental findings"; ( 2 ) a rational management of patients with gallstones depends on an accurate knowledge of the natural history of gallstones; and (3) availability of nonsurgical alternatives to cholecystectomy, like litholitic bile acids, local solvent, and extracorporeal lithotripsy, suggests the need to define more precisely the risk to benefit ratio of different treatments in relation to the natural history of untreated gallstones both in medical and economic terms. In the past, many textbooks have indicated that up to 50% of persons with silent gallstones will develop biliary symptoms or complications, and that complication was the rule for symptomatic gallstones. A number of studies carried out in the last 40 years have tried to define the natural history of gallstones. Unfortunately, many of these studies failed to fulfill the criteria for a correct natural history study: a
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IARS IN LIVER DISEASE-VOLUME
TABLE 3.
Biliary Symptoms in Population Studies Grrll.storle Suhjrc.ts
GREPCO males' (n = 1239) GREPCO females' ( n = 1081)
Nor~gtrll.stor~r Sul>jec~ts
5165
7.7%
23166
34.8%
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7.6% in I 132 sub,jects 20.7% i n 979 sub,ects
careful definition of the population at risk, a large cohort of subjects, prolonged periods of surveillance, and principally, unequivocal characterization of what is being measured. In many instances dyspeptic symptoms were grouped together with biliary symptoms when defining the population at risk and the rate of appearance of symptoms. It has been demonstrated by other^".^."^^^ and by ush that dyspeptic symptoms are not related to the presence of gallstones. As a second point, most studies of the natural history of gallstones have grouped together truly asymptomatic gallstone patients and subjects with infrequent or mild symptoms. The problem is therefore the correct definition of biliary symptoms and, namely, of biliary colic, which is the most frequent and specific symptom caused by gallstones. Bainton et all7 defined symptomatic gallstone disease as a disease in which there was a history of pain in the upper abdomen; Gracie and RansohofPx stated that biliary pain is an episode of upper abdominal pain that was not clearly due to another cause; in the GREPCO4.' and Sirmione studies ,' biliary colic is defined as a pain in the right hypocondrium or epigastrium that has lasted for more than half an hour. When severe, the pain can cause nausea, vomiting, vasomotor phenomena, and is transiently associated in 10 to 20% of patients with raised aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyltranspeptidase and in approximately 5% of cases with clinical features of cholestasis, such as dark urine. According to these criteria, more than two thirds of gallstones detected in epidemiologic studies are asymptomatic (Table 3).
Asymptomatic Patients with Gallstones The natural history of gallstones in patients who have no history of biliary pain or complication is a cru-
cia1 point in order to decide if silent gallstones should be treated prophylactically or left alone. Unfortunately, although none of the studies published so far is ideal, nevertheless, they can provide important information. The most important one is that the natural history of silent gallstones seems to be benign (Table 4 ) . In fact, the available studies show that in a time period ranging from 5 to 24 years the yearly incidence of biliary pain varies from 0.5 to 4%.XX-y2 Examining these studies more in detail, the studies of Comfort et al" and of Ralston et al"' were based on retrospective evaluation of cases, whereas in the study of Newman et al" there is lack of information on the characteristics of the patients; the study of Gracie and RansohoffXXreported on 123 faculty members at the University of Michigan with asymptomatic gallstones followed for I I to 24 years, but the study group consisted almost entirely of white American males. only 13 of the 123 subjects being female; McSherry et al" reviewed the records of 135 patients with silent gallstones, who were subscribers of the Health Insurance Plan of Greater New York and who were followed for a variable period of time (median, 46.3 months) from the date of diagnosis. In the Sirmione study a follow-up study of gallstone patients detected during the first cross-sectional study is in progress. Preliminary data after 5 years indicate a relatively high rate of development of symptoms in previously asymptomatic subjects (15.9% in 5 years); however, most symptoms were observed during the first 2 years and a much lower rate has been observed thereafter (unpublished observation). The observation that the yearly probability of the development of biliary problems appears to decrease with time was observed also in the University of Michigan study,xxwhere the risk of developing symptoms decreased from 2% per year during the first 5 years to 0.5% per year during the third 5 years of observation, and is supported in part by the report of Lund," where the majority of biliary problems, during the 5- to 20-year follow-up, occurred within the first 5 years. A possible question, arising from studies on natural history of silent stones, is if the difference in outcome of subjects with gallstone disease may possibly be related to predictive factors, either demographic or related to the characteristics of gallstones. The available studies show that neither sex and age, nor size, number, and composition of stones, nor nonvisualization of gallbladder have a clear predictive value on the development
TABLE 4. Asymptomatic Gallstone Disease: Natural History Itrc.ider~c~c Rtrrr (B)
No. Subjec,t.s
R1.fc~rrnc.r
Comfort et alxy Ralston and Smith"' Newman et al" Gracie and Ransohoff McSherry et alY' *NR: not reported. $?Median.
*'
112 14 191 123 135
Yrcrrs of' Follow-up
10-20 15-30 2-22 1 1-24 3.89t
Bilicrry Ptrirl tir~d Cornp1ic~trtroil.s
Corrrplic,trtior~s
I9 29 10 16 10.4
4.4 NR:~ NR I 2
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EPIDEMIOLOGY OF GALLSTONE DISEASE-SAMA,
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ET AL
Friedman GD, Kamel WB, Dawber TR: The epidemiology of gallbladder disease: Observations in the Framingham Study. J Chron Dis 19:273-292, 1966. The Coronary Drug Project Research Group. The Coronary Drug project: design, methods and baseline results. Circulation 47 (Suppl I): I , 1973. Sampliner RE, Bennet PH, Comess LJ, et al: Gallbladder disease in Pima Indians: Demonstration of high prevalence and early onset by cholecystography. N Engl J Med 283:13581364, 1970. Bainton D, Davies GT, Evans KT, et al: Gallbladder disease: prevalence in a South Wales industrial town. N Engl J Med 294:1147-1149. 1976. Barbara L, Festi D, Frabboni R, et al: lncidence and risk factors for gallstone disease: The Sirmione study. (Abstr.) Hepatology 8: 1256, 1988. Janzon L, Aspelin P. Eriksson S , et al: Ultrasonographic screening for gallstone disease in middle-age women: Detection rate, symptoms, and biochemical features. Scand J Gastroenterol 20:706-7 10. 1985. Glambek 1. Kvaale G , Arnesjo B. et al: Prevalence of gallstones in Norwegian population. Scand J Gastroenterol 22: 1089- 1094. 1987. Maurer KR. Everhart JE, Ezzati TM, et al: Prevalence of gallstone disease in Hispanic populations in the United States. Gastroenterology 96:487-492, 1989. Bates GC. Brown CH: lncidence of gallbladder disease in chronic hemolyt~canemia (spherocytosis). Gastroenterology 21:104-109, 1952. Jordan RA: Cholelithiasis in sickle cell disease. Gastroenterology 33:952-958, 1957. Soloway RD. Trotman BW. Ostrow JD: Pigment gallstones. Gastroenterology 72: 167-1 82. 1977. Calabrese C , Pearlman DM: Gallbladder disease below the age of 21 years. Surgery 70:413-417. 197 1 . Honore LH: Cholesterol cholelithiasis in adolescent females. Arch Surg 1 15:62-64. 1980. Trotman BW, Soloway RD: Pigment vs. cholesterol cholelithiasis: Clinical and epidemiological aspects. Am J Dig Dis 20:735-740, 1975. Bennion LJ, Grundy SM: Risk factors for the development of cholelithiasis in man. Part 11. N Engl J Med 299:1221-1227, 1978. Thistle JL. Eckhart KL. Nensel RE, et al: Prevalence of gallbladder disease among Chippewa Indians. Mayo Clin Proc 46:603-608. 197 1 . Bennion LJ. Mott DM, Spagnola AM: A biochemical basis for the higher prevalence of cholesterol gallstone in women. (Abstr.) Clin Res 26:496, 1978. Zaki OA, Kamel R: lncidence of cholelithiasis in Egyptians and its relationship with cholesterol. Br J Surg 54:7 13-7 17, 1967. Maki T: Cholelithiasis in the Japanese. Arch Surg 82:599-612. 1961. Yamase H, McNamara JJ: Geographic differences in the incidence of gallbladder disease. Am J Surg 123:667-670. 1972. Diehl AK, Stern MP, Ostrower VS, et al: Prevalence of clinical gallbladder disease in Mexican Americans, Anglo and Black women. South Med J 73:438-441, 1980. Wheeler M, Hills LL, Laby B: Cholelithiasis: A clinical and dietary survey. Gut 11:430-437, 1970. Jackson CE, Gay BC: Inheritance of gall-bladder diaease. Surgery 46353-857, 1959. Van der Linden W. Lindelof G: The familial occurrence of gallstone disease. Acta Genet Stat Med 15: 159-164. 1965. Spiegel E: Beitrage zur klinischen konstitutions pathologie 11. Organ disposition bei ulcus pepticus. Dtsch Arch Klin Med 126:45-60, 1918.
157 Hagberg B, Svernnerholm L, Thoren L: Cholelithiasis in childhood. Acta Chir Scand 123:307-3 15, 1962. Van der Linden W. Simonson N: Familial occurrence of gallstone disease. lncidence in parents of young patients. Hum Hered 23:123-127, 1973. Tesler J: Cholecystitis and cholelithiasis in identical twins. Gastroenterology 7:685-686, 1946. Kennard J: Cholelithiasis in identical twins. N Engl J Med 252:1131-1132, 1955. Laurens H: Cholelithiasis in identical twins. Gastroenterology 29:1096-1097. 1955. Harvald B, Hauge M: A catamnestic investigation of Danish twins: A preliminary report. Dan Med Bull 3:150-158, 1956. Doig RK: Illness in twins 111. Cholelithiasis Med J Aust 2:716-717, 1957. Gilat T. Feldman C , Halpern Z, et al: An increased familial frequency of gallstones. Gastroenterology 84:242-246. 1983. Barbara L, Festi D. Morselli Labate AM, et al: The Sirmione study: Familial frequency of gallstone disease. (Abstr.) Hepatology 4: 1086, 1984. Scragg RKR, McMichael AJ. Baghurst PA: Diet, alcohol and relat~veweight in gallstone disease: A case-control study. Br Med J 288:1113-1119. 1984. Knowler WC, Carraher MJ. Petitt DJ: Diabetes mellitus, obesity and cholelithiasis. In: Capocaccia L. Ricci G. Angelico F, Angelico M, Attili AF (Eds): Epidemiology and Prevention of Gallstone Disease. Lancaster, MTP Press. 1984. pp 85-9 1 . Jorgensen T: Gallstones in a Danish population. Relation to weight. physical activity, smoking. coffee consumption and diabete mellitus. Gut 30:528-534, 1989. Diehl AK. Haffner SM. Knapp JA. et al: Dietary intake and the prevalence of gallbladder disease in Mexican Americans. Gastroenterology 97: 1527-1533, 1989. Hanis CL. Ferrell RE, Tulloch BR, et al: Gallbladder disease epidemiology in Mexican Americans in Starr County. Texas. Am J Epidemiol 122:820-829. 1985. Diehl AK, Rosenthal H. Hazuda HP, et al: Socioeconomic status and the prevalence of clinical gallbladder disease. J Chron Dis 38:1019-1026, 1985. Scragg RKR. McMichael AJ. Seamark RF: Oral contraceptives, pregnancy, and endogenous oestrogen in gallstone disease. A case-control study. Br Med J 288:1795-1799, 1984. Layde PM, Vessey MP, Yeates D: Risk factors for gall-bladder disease: A cohort study of young women attending familial planning clinics. J Epidemiol Community Health 36:274-278, 1982. Royal College of General Practitioners Oral Contraception Study: Oral contraceptives and gallbladder disease. Lancet 2:957-959, 1982. Williams CN, Johnston JL, Weldon KLM: Prevalence of gallstones and gallbladder disease in Canadian Micmac Indian women. Can Med Assoc J 117:758-760, 1977. Jorgensen T: Gallstones in a Danish population: fertility period, pregnancies, and exogenous female sex hormones. Gut 29:433-439, 1988. Kern F, Everson GT, De Mark B, et al: Biliary lipids, bile acids and gallbladder function in the human female. Effect of pregnancy and the ovulatory cycle. J Clin Invest 68:12291242, 1981. Everson GT, McKinley C , Lawson M , et al: Gallbladder function in the human female: Effect of the ovulatory cycle, pregnancy and contraceptive steroids. Gastroenterology 82:711719, 1982. Sarles H, Chabert C , Pommeau Y, et al: Diet and cholesterol gallstones. A study of 101 patients with cholelithiasis compared to 101 matched controls. Am J Dig Dis 14:531-534, 1969.
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EPIDEMIOLOGY OF GALLSTONE DISEASE-SAMA,
SEMINARS IN LIVER DISEASE-VOLUME Pixley F. Mann J: Dietary factors in the aetiology of gallstones: A case-control study. Gut 29: 15 1 1-15 15. 1988. Attili AF. GREPCO: Dletary hablts and cholel~thiasis.In: Capocaccia L. Ricci G . Angelico F. Angelico M. Attili AF (Eds). Epidemiology and Prevention of Gallstone Disease. Lancastrr, MTP Press, 1984. pp 175-1 81. Barbara L. Cornia GL. Festi 11. et al: Dietary hablt and incidence of gallstone\ in the Sirmione study. (Ahstr.) Hepatology 10:736. 1989. Boston Collahoratlve Drug Surveillance Program: Oral contraceptives and venous thromboemholic disease. surgically confirmed gallbladder di\ease. and breast tumors. Lancet 2: 13991404. 1973. Stolley PD, Tonascia JA. Tockman MS. et al: Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol 102:197208. 1975. Howat JMT. Jones CB. Schof~eldPF: Gallstones and oral contraceptives. J Int Med Res 33:59-62. 1975. Kern F, Everson GT. De Mark B, et al: Biliary lipids. bile acids, and gallbladder function in the human female: Effect of contraceptive steroids. J Lab Clln Med 99:789-805, 1982. Braverman DZ. Johnson ML, Kern F: Effect of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 302:362-364. 1980. Grundy SM. Ahrens EM Jr, Salen G , et al: Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J Lipids Res 13:53 1-55 1 . 1972. Palmer RH: Prevalence of gallstones in hyperllpldemia and incidence during treatment with clofibrate andlor cholestyramine. Trans Assoc Am Physicians 91 :424-428. 1978. Coronary Drug Project Research Group: Gallbladder di\ease as a slde eftect of drugs ~nflucncinglipid rnetaboli\~ii:Expcriencc in the Coronary I>rug Project. N Engl J Med 296: 11861190. 1977. Gross DMB: A statistical \tudy oI'cholelithla\is. J Pathol Bacteriol 32:503-526. 1929. Liebcr MM: The incidence of gallstones and thelr correlation with other diseases. Ann Surg 135:394-405. 1952. Newman HF. Northup JD: The autop\y incidence of gallstones. Int Abstr Surg 109: 1-13. 1959. Honore LH: The lack of a positive as\ociation between symptomatic cholesterol cholelithiasls and clinical diabetc\ mellitus: A retrospective study. J Chron Dis 33:465-469. 1980. Ahlberg J. Angelin B. Einar\son K: Prevalence of gallbladder disease in hyperlipoprotc~nc~iiia.Dig I>i\ Sci 24:459-464. 1979. Petitti DB, Friedman GD. Klatsky AL: Association of a history of gallbladder disease with a reduced concentration of high-density-lipoprotein cholesterol. N Engl J Med 304: 13961398, 1981.
10, NUMBER 3, 1990
Scragg RKR, Calvert GD, Oliver JR: Plasma lipids and insulin in gallstone disease: A case-control study. Br Med J 289521525, 1984. Angelin B: Cholesterol and bile acid n~etabolismin normoand hyperlipoproteinemia. Acta Med Scand Suppl 610: 1 . 1977. Angelin B, Einarsson K. Hellstrom K, et al: Elimination of cholesterol in hyperlipoproteinemia. Clin Sci Mol Med 5 1: 393-397. 1976. Nervi FO. Dietschy JM: Ability of six different lipoprotein fractions to regulate the rate of hepatic cholesterogenesis in vivo. J Biol Cheni 250:8704-87 l I , 1975. Boyd GS. Onajobi FD: Control of cholesterol biosynthesis by a plasma apolipoprotein. Nature 22 1:574-575. 1969. Halloran LG, Schwartz CC. Vlahcevic ZR. et al: Evidence for high-density lipoprotein-free cholesterol as the primary precursor for bile acid synthesis in man. Surgery 84:l-7, 1978. Cohen S. Kaplan MM, Gottlieb L, et al: Liver disease and gallstones in regional enteritis. Gastroenterology 60:237-241, 1971. Baker AL, Kaplan MM. Norton RA. et al: Gallstones in inflammatory bowel disease. Am J Dig Dis 19:109-1 12, 1974. Hcaton KW. Read AE: Gallstones in patients with disorders of the terminal ileum and disturbed bile salt nietabolisnl. Br Med J 3:494-496. 1969. Gracie WA. Kansohoff DF: The natural history of gallstones: The Innocent gallstone is not a myth. N Engl J Med 307:798800. 1982. C o m h r t MW. Gray HK, Wilson JM: The silent gallstone: A ten to twenty year follow-up study of 112 cases. Ann Surg 128:913. 1948. Ralston DE. Smith LA: The natural history of cholelithiasis: A 15 to 30-year follow-up of 116 patients. Minn Med 48:327332. 1965. Newman HF. Northup JD. Rosenbluni M. Abrams: Complication\ of cholelithiasis. Am J Gastroenterol 50:476-496. 1968. McSherry CK, Ferstenberg H, Calhoun WF, et al: The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg 202:59-63, 1985. Lund J: Surgical indications in cholelith~asis. Ann Surg 151:153-162. 1960. Wenckert A. Robertson B: The natural course of gallstone disease: Eleven-year review ol' 87 1 nonoperated cases. Gastroenterology 50:376-381. 1966. Gomand L, Vandenbroucke J , De Groote J: Die natuurlijke evolutie van colelithiase. Tijdschr Gastroenterol 9594-601, 1966.
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158
10, NO. 3, 1990
Epidemiology and Natural History of Gallstone Disease
Gallstone disease is a major public health problem in the Western world from both a medical and a financial perspective. In the United States more than half a million cholecystectomies were performed in 1987,' and direct costs related to gallbladder disease can be roughly estimated at $3 billion annually. In Europe, more than 25,000 women undergo cholecystectomy per year in England and Wales,' and recent population studies in Denmark and Italy have shown that gallstone disease is detected in more than 10% of the adult population.;'-" Because reliable epidemiologic studies can provide important information regarding etiology, risk factors, natural history, and, it is hoped, prevention of diseases, many clinicians in the last decade have focused their attention on the epidemiology of gallstones. Two additional facts have further supported this renewed interest in gallstones: the spread of ultrasonography techniques, which have led to the discovery of increasing proportions of asymptomatic gallstone cases and the availability of new therapeutic nonsurgical approaches, such as litholitic bile acids, local solvents, and lithotripsy. Historically, Morgagni,' in the 18th century, from his autopsy studies on gallstone patients, observed that the prevalence of gallstone disease increased with age, advanced the hypothesis that obesity could be a risk factor for gallstones and stated some 200 years ago, that gallstones can remain asymptomatic for a whole life time. All these observations have been confirmed by recent epidemiologic studies.
EPIDEMIOLOGY OF GALLSTONES Prevalence and Incidence There is convincing evidence that the prevalence of gallstone disease is on the increase. At present, most of the data on the prevalence of the disease are still based
From tho 1,stiruro di Clinic.tr Mrdic.tr r Grr.strorrr~~rologitr. Urli\~crsirirdi Rologr~cr,Itcrly: Dil~trrtimer~to di Orlc~ologitrSl~erirnrnrtrlr r Clirlic.tr. Ftrc.oltti di Mc,dicincr r Chirurgitr di Catrrr~:trro. Urltrc,r.\itti di Keggio Calahritr. Ittrly, crnd Isrituro Slcprriorc, di Snnitir Romcr, Ituly.
Reprint requests: Dr. Sama, Istituto di Clinica Medica e Gastroenterologia. v. Massarenti 9 40138 Bologna, Italy.
on autopsy studies. Although data from autopsy studies should be interpreted with caution, since reasons for autopsy may be related to the risk of gallstone disease and may therefore over- or underrepresent the true frequency of the disease in the population, these studies had the great merit of indicating racial and geographic differences in the prevalence of gallstones. Prevalence seems to be higher in the Western world and South America, and lower in Eastern countries and Africa. '- However, compared with the last century, the prevalence of gallstones seems to be increasing not only in affluent westernized countries, but also in countries that are becoming westernized. Gallstone disease was previously rare in Eastern countries and stones were predominantly of the pigment type, but since World War 11, cholesterol-rich gallstones have become much more common and total stone prevalence has escalated. " Other studies on the prevalence of gallstones have been based on clinically diagnosed cases. Some of them derived from a selected series of patients, mainly from hospital studies.'' Hospital series, however, have the same bias as observed in autopsy studies, that is, of not being representative of the general population. Others were based on population studies of statistically valid random samples of the general population. Among the latter, the two major published studies were not primarily directed toward gallstone disease. The Framingham studyIJ investigated the prevalence and 10-year incidence of clinically diagnosed gallstones, 5,209 subjects who took part in the Heart Disease Epidemiology Study. The age at entry was 30 to 59 years. An overall prevalence of 3.9% was found, and the incidence, calculated after 10 years, was 4.5%. The Coronary Drug Project" found an overall clinical prevalence of 3.9% in an age span of 30 to 64 years. Because it is well established that a large proportion of gallstones remain asymptomatic and are therefore often ignored for many years, even until death, studies based on clinically diagnosed cases should be interpreted with caution, since they are representative of the clinical and not of the true prevalence. Realistic information on the occurrence of gallstones in a given population can derive only from systematic population-based studies, in which everyone undergoes the same diagnostic test for gallstones. In the past, the major problem has been the diagnostic test. In fact, only oral cholecystography was
''
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149
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CLAUDIA SAMA, M.D., ANTONIO MARIA MORSELLI LABATE, Ph.D., FRANCESCO TARONI, M.D., and LUlGl BARBARA, M.D.
SEMINARS IN LIVER DISEASE-VOLUME
available and therefore, because of the difficulty and expense of applying radiographic procedures in population surveys, it was used in very few studies. Sampliner et all" studied symptomatic and asymptomatic gallbladder disease in Pima Indians. They found an overall prevalence of 48.6%. This study showed a dramatic increase of gallstone prevalence in females from 12% in the 15to 24-year age group to 73% in the 25- to 34-year age group and older. Bainton and colleagues17 performed oral cholecystography on a weighted sample of the population of an industrial town in South Wales. Reported prevalence of gallstone disease was 9.2%. More recently, echography appeared, showing its fundamental role in the diagnosis of gallstone disease. Ultrasonography, besides having a high sensitivity and specificity compared with the traditional x-ray proccdures, is simple. safe, and noninvasive and therefore appears to be the better diagnostic tool for epidemiologic studies. Two Italian studies initiated the echographic era: the GREPCO".i and the Sirmione studies." The GREPCO study was based on two occupational populations of 108 1 women and 1289 men. The reported prevalence of gallstone disease in the age span 20 to 64 years was 9.4% and 8.%, respectively. The Sirmione study is a prospective study on the incidence and risk factors of gallstone disease in the town of Sirmione in the North of Italy. The first cross-sectional study on 1930 subjects aged 18 to 65 years has shown an overall prevalence of gallstone disease of I I%." In order to assess the incidence of gallstones, the population of Sirmione was again screened 5 years later. The cumulative 5 years' incidence was 3% . I " Recently, other studies reporting the prevalence of gallstone disease in general population samples assessed by ultrasonography have been co~npletedin Europe'. I". "' and in the United States." Data on prevalence of gallstone disease in Europe is shown in Table 1 . Maurer et al," comparing Hispanic populations in the United States, found the highest prevalence in Mexican Americans (23.2% in women and 7.2% in men) in comparison with Cuban Americans (15.4% in women, 4.2% in men) or Puerto Ricans (13.5% in women, 4% in men). In 1985 a Multicenter Italian Study on Epidemiology of Cholelithiasis (MICOL) was initiated in Italy. Altogether 54,000 subjects aged 30 to 69 years were TABLE 1.
Females GKEPCO' Sirmione" Sorpen\en3 Janzon et al"' Glatnbek et al'" Males
GREPCOi Sirmione" Soreensen' Glanibek et al'"
10, NUMBER 3, 1990
sampled in 18 centers from 10 different Italian regions and studied with ultrasonography." Preliminary data are now available. The mean observed prevalence was 9.5% in males and 19% in females. (unpublished observation).
Risk Factors The prevention of cholelithiasis, which is still at a very early stage, depends on a clear understanding of events concerning pathogenesis and risk factors. Although many factors have been considered in the past as well as in recent years, the current literature about epidemiology of gallstone disease makes it very difficult to support clinical observations with statistics. However, most of these factors are supported by prevalence data or clinical studies. Risk factors for pigment stones are mainly related to concomitant pathologic conditions, like hyperhemolysis due to genetic defects"." or infections, whereas risk factors for cholesterol gallstones are more related to metabolic conditions. We will now consider the major putative risk factors for gallstones, particularly with regard to those observed in the Western world, where cholesterol gallstones predominate
Both prevalence and incidence of gallstone disease increase with age. The previous observation of Morgagni7 has been confirmed by the majority of epidemiologic studies. Gallstones are very seldom found in children, and in that age group are mainly associated with hemolytic causes." When comparing several series, less than 5% of cholecystectomies are performed under the age of 20 ears.'^-'^ In Sirmione, of 135 subjects between 18 and 21 years of age, stones were detected in only one subject. The Framingham Study'" has shown that both prevalence and incidence of gallstone disease increased with age. In this study the majority of persons with gallstone disease were diagnosed during the sixth and seventh decades of life. In a study conducted in a South Wales population, Bainton and colleagues,'' on the contrary, failed to find a positive correlation between gallstones and age.
Prevalence of Gallstone Disease Assessed by Ultrasonography in Europe
ltaly ltaly Denmark Sweden Norway ltaly ltaly Denmark Norway
'@Agespan: 60-64 years. 'IAge span: 18-29 and 50-65 years. $Age: 4 8 and 53 years.
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15 0
This is probably due to the fact that the age span considered in this study (45 to 69 years) was not wide enough to allow sufficient distribution of subjects in different age groups. In recent years, both the GREPCO and the Sirmione studies,'-" as well as all studies conducted in the echographic era,3.?0.3 showed that the prevalence of gallstones increased steadily with age in both sexes. Moreover, in the Sirmione Study'' the 5-year incidence rate was about four times higher in the age span 40 to 69 years than in younger subjects. Interestingly, the cutoff point between relatively low and high incidence rate seems to be 40 years, once again confirming the old aphorism on the major risk of gallstone disease: "female, fair, fat, and forty." This finding supports also the common wisdom that the risk of developing gallstones is really much higher in the elderly than in other age groups, which derives from extrapolation of prevalence data. Sex
Most epidemiologic studies have shown that, at least in the Western world, females have a higher frequency of gallstones than males. A female preponderance has been, in fact, observed in several studies in the past, 14.10.1?.?7 29 However. the male to female ratio seems to have changed from the early reports. which showed figures of 1:4-6, to more recent studies where the ratio ' ~ . trend ' ~ has been confirmed by the is 1:2 or l e ~ s . ' ~ .This prevalence studies in the echographic era.' " "I-" Female preponderance has been observed in all age groups. although most population studies have shown that female and male prevalence rates were more similar in the older age groups (Table 2). Female preponderance has not been observed in subjects with pigment stones. where the female to male ratio is approximately 1: 1 .27 The causes of sex-related differences in prevalence of cholesterol gallstones are not fully understood at present. Pregnancy and sex hormones could be involved by altering biliary secretion'" or gallbladder motility, or both. Genetic Factors
The importance of genetic factors in the pathogenesis of cholelithiasis, although generally recognized, is
TABLE 2. Femalelmale Ratio of Prevalence of Gallstone Disease in Different Studies
20-29
Framinghaml' South Wales1' GREPCOJ-5 Sirmione" Jorgensen'
I. I 2.6 -
*Age span 50-62 years. **Age span 45-49 years.
30-39
40-49
50-59
60-69
4.3 -
3.1 2**
2.3* 2.8
1.3
2.9 2.2 2.8
1.6 1.7 4.1
1.2 2.4 2.2
-
-
1.7
151
very seldom widely discussed in the recent literature, probably due to the lack of extensive and unequivocal studies. Undoubtedly, both autopsy and population StudieSX-14.31have clearly demonstrated the existence of racial differences as far as prevalence of gallstones is concerned. Some of these differences can be explained by environmental factors. as shown by the increased prevalence observed in Japan after World War 11, which doubtless related to the westernization of the country, or by the change in prevalence after immigration into high prevalence countries. "."." However, at least two examples are consistent with the fact that a diathesis for gallstone disease exists in certain ethnic groups. The first is the strikingly high prevalence of gallstones among American Indian populations (more than 70% over the age of 50 years) which probably represents the highest prevalence detected in the world.'" The second example is a recent study on gallbladder disease conducted in Mexican-American, black and white women from the United States. Diehl et al" found that Mexican-American women had a prevalence of gallstone disease of 14.7% in comparison to 9% in white and 4.5%. in black women. These differences in prevalence are not related to age distribution. obesity, or other risk factors. It is generally believed that cholelithiasis has a higher frequency among relatives of patients. However, very few studies have attempted to confirm this hypothesis. Most studies were ~ncontrolled'"~ and although some of them have shown a familial aggregation of the disease, they are influenced by bias as indicated by Spiegel" in 19 18: "individuals with a disease tend to be more aware of family members with the same disease." If inheritance is responsible fix the concentration of cases in the families of gallstone patients, this should be particularly evident for cases detected when young. This has been shown by Hagberg et al" and Van der Linden et al.'" Unfortunately, there are very few studies on cholelithiasis in twins in the medical literature. Apart from some case report on monozygotic twins," " other studies were based only on clinically diagnosed cases," or studied twins admitted to hospital^,'^ and were not able to substain a genetic explanation for the etiology of cholelithiasis. Recently. Gilat and coworkers"" have studied prospectively the frequency of gallstones in 17 1 first-degree relatives of patients with proven gallstones, compared with 200 matched controls. All subjects were studied by oral cholecystography. Gallstones were found in 20.5% of the family group and in 9% of the control group. These differences were statistically significant after controlling for known risk factors. In the Sirmione study 303 pairs of parents-sonsldaughters have been identified among the 1930 subjects participating in the study and submitted to ultrasound examination for detecting gallstones. The children were divided into two groups according to the presence or absence of gallstone in their parents. The relative risk for gallstones was significantly higher ( R R 3.3; 95% CL = 0.97-1 1.47) in sons and daughters of parents with gallstones, controlling for age and other possible confounding factor^."^ These studies, however, need further investigation, because most of the
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ET AL
EPIDEMIOLOGY O F GALLSTONE DISEASE-SAMA.
SEMINARS IN LIVER DISEASE-VOLUME
findings can also be explained by environmental factors of cholelithiasis; family dietary habit could be a factor. However, the results of these studies, although not proving the real importance of genetic factors in gallstone disease, do not exclude it. Genetic and environmental factors are not mutually exclusive and may coexist. It is hoped that in the future the use of ultrasonography in conjunction with formal genetic family studies will give a real insight into the problem.
Obesity Many clinical and epidemiologic studies indicate that cholesterol gallstones are more common in obese subjects. In a case-control study, Scragg et alJxfound that body mass index (BMI = weightiheight'), was significantly higher in female patients with gallstone than in males. The same results were observed in most population studies. In the Framingham study" women with gallstones at entry and those who developed gallstones during the study had an average relative weight higher than gallstone-free women; these differences were not observed in men. Knowler et al,'" in the study on Pima Indians, failed to find an association between obesity and gallstones in men, but the relationship between BMI and gallstone disease was statistically significant (p < 0.05) in women. In the GREPCO, Jorgensen, and Diehl studi e s , ~ . a~significant ~ . ~ ~ positive association between BMI and the presence of gallstones was observed in women but not in men. Other population studies, based on clinical prevalencei' or ultrasonography-assessed prevalence," found that both men and women with gallstones had a higher BMI than nongallstone subjects. Moreover the Sirmione study showed that the risk of developing gallstones for currently obese subjects is higher in the lower age groups and that incidence is about three times higher in obese than in nonobese subjects.'" There are at present no clear explanations for these discrepancies. The populations studied may differ in terms of the prevalence of obesity; different investigators can use different definitions of obesity, making comparisons among studies difficult; and finally BMI may not be as good an indicator of obesity in men as in women, since the index could be the same in a subject who is really obese as in a subject who is heavily muscled. The link between obesity and cholesterol gallstones is supersaturated bile. Obesity raises the saturation of bile by increasing biliary secretion of cholesterol, the latter depending probably on a higher synthesis of cholesterol in obese subjects.
Parity Pregnancy is thought by many investigators to promote gallstone formation. Most cohort studies of clinically diagnosed gallstone^"."^'^ as well as case-control showed a positive correlation between gallstudies'" '-' stones and number of pregnancies. Two and ~' to show this corstudies on American I n d i a n ~ ' " . failed relation. Among recent studies investigating the overall prevalence of gallstones in free-living populations, a sig-
10, NUMBER 3, 1990
nificant increase in gallstone prevalence was found in women who have had multiple pregnan~ies.~.".'"oth GREPCO and Sirmione studies have also demonstrated that the increase in the relative risk due to pregnancy is higher among younger than among older women. Pregnancy could influence gallstone formation in several ways. Composition of bile may be altered adversely by hormonal changes during pregnancy." Recent studies have shown sluggish gallbladder emptying during the third trimester of pregnancy;'" this could induce gallstone formation by altering bile acid enterohepatic circulation and promoting retention of cholesterol crystals, a prerequisite for gallstone formation. In addition, rapid weight variation during and after pregnancy can influence biliary lipid secretion.
Among environmental factors that can influence gallstone formation, diet has undoubtedly a prominent role. This suggestion derives from well-known cultural and geographic differences, which show a higher prevalence of gallstone disease in developed, westernized countries, which have a relative overconsumption of calories, whereas gallstones are rare in primitive rural communities. It is well known that since World War 11, an increasing incidence of gallstone disease has been observed in Japan, with relation to change in dietary habits toward a "Western style."" Moreover, prevalence of gallstones increases in subjects moving from a low to a high frequency area.".3' Unfortunately, this suggests only that something related to the westernized diet possibly favors the development of gallstones. The putative factors are highly purified carbohydrates and animal fats, together with decreased intake of dietary fiber and vegetable fats. Several investigators have studied specific aspects of diet in order to assess dietary influences on gallstone prevalence, but there are many methodologic difficulties that limit the validity of nutritional data and that should be considered when interpreting reports on nutritional studies. Moreover, until recently, the majority of articles evaluating the relationships between gallstone and diet were based on autopsy studies or symptomatic gallstones or hospital studies. However, owing to the fact that the majority of gallstones are asymptomatic, we have no information on the dietary habits of asymptomatic patients. In the past, studies in Franceh' showed a higher caloric intake in subjects with gallstone than in controls. On the contrary, data on eating habits reported in the Framingham study" failed to reveal an association between the presence of clinically diagnosed cases of gallbladder disease and daily intake of fat, protein, and cholesterol. A slight, though not significant, trend, suggesting that persons who consumed less alcohol ran a higher risk of subsequent gallbladder disease, was observed in the Framingham study. A case-control study from Australia" showed that increased intake of simple sugars was associated with an increased risk of gallstones as well as an increased intake of energy or fat, although the two latter findings were significant only in young subjects; in both sexes, in-
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ET AL
creased intake of alcohol was associated with a decreased risk of developing gallstones. Diehl and coworkers," in a population study on clinical gallstone disease in Mexican Americans and non-Hispanic whites, found that women with the highest intake of total fat and linoleic acid had a reduced risk of gallbladder disease, although an opposite trend was observed in men. In a case-control study on dietary intake, in 121 women with gallstones, Pixley et alh' found an appreciably lower frequency of gallstones among vegetarian women compared with nonvegetarian women. In the GREPCO study,"j women with gallstones showed a reduced intake of sugar, cheese, meat, and bread. In this study, women with a higher daily wine consumption showed a higher, although not significant, prevalence of gallstones than women with low or no consumption of wine. Finally in the Sirmione Study"' no difference was observed in the daily intake of energy, protein, total fat, and carbohydrates between gallstone and nongallstone subjects. A lower intake of dietary fiber was associated with a higher incidence of gallstones and a slightly higher alcohol consumption was observed in nongallstone subjects, confirming previous results. From the reported data, it appears that the relation of specific dietary constituents to gallbladder disease risk is still presumed but not proved. In analyzing studies that have considered diet as a risk factor, it is important to bear in mind the existence of methodologic problems related to the difficulty to obtain an accurate dietary history, to the relationship between the time in which the study was done and the time when gallstones have developed, and finally to the possible dietary changes in symptomatic patients. Once again, only cohort studies employing gallbladder ultrasonography will possibly elucidate the relation between diet and gallstones.
Drugs I t has been indicated that some drugs can raise the saturation of bile and hence the danger of gallstones. We will discuss below oral contraceptives and fibric acid derivatives. In the 1970s several studies showed an increased frequency of gallstone disease among women using oral contraceptives. In 1973 the Boston Collaborative Drug Surveillance Programhs published the results of a casecontrol study on gallbladder disease. They found a significant higher relative risk for gallstones (based on diagnosed cholelithiasis andlor cholecystectomy) among women 20 to 34 years old using oral contraceptives. The risk was not related to the duration of oral contraceptive use. Elevated risk for gallstone disease in users of oral contraceptives was also reported in three subsequent case-control studies.". '". h7 More recent reports, derived from prospective cohort studies failed to confirm the association between oral contraceptives and cholelithiasis,3J.ss.sh If we look at the studies published in the last 5 years, results are still conflicting. A case-control study by Scragg et als4 found that use of oral contraceptives
153
was associated with an increased risk of developing gallstones among young subjects but with a decreased risk among older subjects. Both GREPCO and Sirmione studies,'.' on 1081 and 1047 women, respectively, who were evaluated by ultrasonography, found no difference in frequency of gallstone disease in women who ever used and in those who never used estroprogestinic drugs. Finally, from a cross-sectional study of gallstone disease ascertained by ultrasonography in a Danish population, Jorgensen5' reported that use of oral contraceptives was significantly associated with gallstone disease in univariate analysis and that the risk was higher in older than in younger women. A possible association between gallstone and oral contraceptives has a biologic basis. In fact oral contraceptives can increase cholesterol secretion, decrease bile acid secretion, and impair gallbladder emptying," although other authors have not confirmed these findi n g ~There . ~ ~ is no clear explanation for the conflicting results reported in epidemiologic studies. Many studies have shown an increased risk of gallstones in young women, and the Royal College of General Practitioners StudyShhas shown an increased risk only for the first few years after the patients began taking the pill. They showed also a doubling of the risk when 100 or 150 p g estrogen preparations were used compared with 50 p g preparations. Ascertainment bias is also possible in studies based on clinical prevalence because of the increased medical suspicion related to the previously published reports of this association or because women taking pills are submitted to more frequent medical check-up for routine follow-up, leading to an increased probability of diagnosis. Moreover, results from cohort studies on clinically diagnosed gallstones may very well be inaccurate, since more than half of all subjects harboring gallstones are unaware of it and are therefore considered nongallstone cases. Only prospective studies investigating the incidence of gallstones on large cohorts of women of different ages and using different dosages of drugs will answer the question regarding the effect of estroprogestinic drugs in gallstone disease. Clofibrate and related drugs, which have been used for the control of hyperlipidemia, enhance the saturation of bile by increasing biliary secretion of cholesterol and decreasing synthesis of bile acid^.^" This effect has been confirmed by several epidemiologic studies, which have clearly shown an increased risk of gallstone disease in subjects using clofibrate to lower serum lipid level^.^'."
Other Diseases as Risk Factors Diabetes Autopsy studies indicate that prevalence of gallstone disease is slightly increased in diabetic s ~ b j e c t s . ~ ' - ~ ~ Epidemiologic studies conducted in vivo have, however, given conflicting results. A case-control study in Newfoundland compared the prevalence of known diabetes in 775 subjects of both sexes undergoing cholecystectomy for cholesterol cholelithiasis with 1308 agematched controls undergoing other surgical procedure^.^'
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EPIDEMIOLOGY O F GALLSTONE DISEASE-SAMA,
In this study an inverse relationship, not statistically significant, was found between diabetes and cholelithiasis. Sampliner in the earlier Pima Indian studyLhfound no association between diabetes and gallstones. whereas in the same population, Knowler et alJ" provided later evidence for a relationship of diagnosed gallstone disease, not only with diabetes but also with impaired glucose tolerance. Also Diehl et al" reported that diabetic Mexican-American, black and white females had a higher prevalence of gallstone disease than subjects without diabetes, controlling for other possible risk factors as age and obesity. In contrast, the two Italian studies, GREPCO and Sirmione,'-" and the Danish studyXVailed to observe an association between diabetes and gallstones. Differences observed in differential studies can be related perhaps to methodologic problems. In fact, the diagnostic criteria for diabetes are widely different in different studies. Some studies are based only on known diabetes; others, like the Pima study, have also used a glucose tolerance test. Both in GREPCO and Sirmione studies sub-jects with a known history of diabetes or with fasting blood glucose levels higher than 140 mgldl were defined as diabetic. A second problem concerns the diagnosis of gallstone disease. In the majority of published studies gallstone cases were clinically diagnosed, which very often are not representative of the true prevalence of the disease.
10. NUMBER 3, 1990
show an increased frequency of gallstones; however, an association between hypertriglyceridemia and gallstone disease has been observed in both sexes. The mechanisms underlying the raised plasma triglyceride levels in gallstone pati& are not fully elucidated, although the observation that patients with types IIb and IV hyperlipoproteinemia, who have an increased prevalence of gallstones, have an increased triglyceride synthesisx"and an increased hepatic cholesterol synthesis," suggests that this could be the explanation in gallstone patients. Also, the inverse association between plasma total and HDL cholesterol is not easily explained. o n e possible explanation derived from studies in ratsx'-" is that a lowered ~ l a s m atotal and HDL cholesterol could result in increascd cholesterol synthesis by the liver because high levels induce an inhibition of the synthesis itself. Another possible explanation for the inverse relationship between HDL levels and gallstones is that free cholesterol in HDL is preferentially metabolized to bile acids."
Ileal Diseases Cholelithiasis has been associated with terminal ileal diseases. Both clinical seriesx'."'and case-control studies" confirmed the association. The biologic explanation for this association is that patients with ileal disease and ileal resection have an increased loss of bile salts in the feces and diminished bile acid pool size.
Hyperlipidemia Hemolytic Anemias Bile saturated with cholesterol is recognized as a precursor to cholesterol gallstone formation. Several investigators have therefore analyzed serum lipid levels in order to try to elucidate the possible changes in lipid metabolism associated with the formation of gallstones. Ahlberg et aI7' compared serum triglyceride and serum cholesterol levels in 457 gallstone patients with those of 230 control patients. No association was found between serum cholesterol levels and gallstone disease, while gallstone patients older than 40 years had higher serum triglyceride levels than did controls. The presence of gallstone disease is also positively associated with type IV77.78and type IIb7' hyperlipoproteinemia, both of which are characterized by an increase in concentration of triglyceride-rich very low density lipoproteins. In a cross-sectional study of patients with gallstone disease, Petitti et a17' reported an inverse relationship between gallbladder disease and HDL levels. A recent case-control study by Scragg et a17" confirmed these results. They found, using a multivariate method of analysis, that increased triglyceride concentrations were associated with an increased risk of gallstones in young subjects only; they found also that increased plasma total and high density lipoprotein (HDL) cholesterol concentrations were associated with a decreased risk of gallstones. In the GREPCO study,' using a multiple logistic regression analysis, a positive correlation was found between presence of gallstones and high serum triglyceride levels and with decreasing total (and low density lipoprotein) cholesterol. Also in the Sirmione study,' hypercholesterolemic subjects did not
He~nolyticanemias are associated with gallstone disease of the pigment type."-'" The possible explanation is probably an increased production and biliary secretion of bilirubin, which can induce gallstone formation.
NATURAL HISTORY OF GALLSTONE DISEASE Studies on the natural history of gallstones have received considerable attention in recent years, owing to the fact that: ( I ) the widespread use of ultrasonography results in asymptomatic gallstones being identified more frequently as "incidental findings"; ( 2 ) a rational management of patients with gallstones depends on an accurate knowledge of the natural history of gallstones; and (3) availability of nonsurgical alternatives to cholecystectomy, like litholitic bile acids, local solvent, and extracorporeal lithotripsy, suggests the need to define more precisely the risk to benefit ratio of different treatments in relation to the natural history of untreated gallstones both in medical and economic terms. In the past, many textbooks have indicated that up to 50% of persons with silent gallstones will develop biliary symptoms or complications, and that complication was the rule for symptomatic gallstones. A number of studies carried out in the last 40 years have tried to define the natural history of gallstones. Unfortunately, many of these studies failed to fulfill the criteria for a correct natural history study: a
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IARS IN LIVER DISEASE-VOLUME
TABLE 3.
Biliary Symptoms in Population Studies Grrll.storle Suhjrc.ts
GREPCO males' (n = 1239) GREPCO females' ( n = 1081)
Nor~gtrll.stor~r Sul>jec~ts
5165
7.7%
23166
34.8%
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7.6% in I 132 sub,jects 20.7% i n 979 sub,ects
careful definition of the population at risk, a large cohort of subjects, prolonged periods of surveillance, and principally, unequivocal characterization of what is being measured. In many instances dyspeptic symptoms were grouped together with biliary symptoms when defining the population at risk and the rate of appearance of symptoms. It has been demonstrated by other^".^."^^^ and by ush that dyspeptic symptoms are not related to the presence of gallstones. As a second point, most studies of the natural history of gallstones have grouped together truly asymptomatic gallstone patients and subjects with infrequent or mild symptoms. The problem is therefore the correct definition of biliary symptoms and, namely, of biliary colic, which is the most frequent and specific symptom caused by gallstones. Bainton et all7 defined symptomatic gallstone disease as a disease in which there was a history of pain in the upper abdomen; Gracie and RansohofPx stated that biliary pain is an episode of upper abdominal pain that was not clearly due to another cause; in the GREPCO4.' and Sirmione studies ,' biliary colic is defined as a pain in the right hypocondrium or epigastrium that has lasted for more than half an hour. When severe, the pain can cause nausea, vomiting, vasomotor phenomena, and is transiently associated in 10 to 20% of patients with raised aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyltranspeptidase and in approximately 5% of cases with clinical features of cholestasis, such as dark urine. According to these criteria, more than two thirds of gallstones detected in epidemiologic studies are asymptomatic (Table 3).
Asymptomatic Patients with Gallstones The natural history of gallstones in patients who have no history of biliary pain or complication is a cru-
cia1 point in order to decide if silent gallstones should be treated prophylactically or left alone. Unfortunately, although none of the studies published so far is ideal, nevertheless, they can provide important information. The most important one is that the natural history of silent gallstones seems to be benign (Table 4 ) . In fact, the available studies show that in a time period ranging from 5 to 24 years the yearly incidence of biliary pain varies from 0.5 to 4%.XX-y2 Examining these studies more in detail, the studies of Comfort et al" and of Ralston et al"' were based on retrospective evaluation of cases, whereas in the study of Newman et al" there is lack of information on the characteristics of the patients; the study of Gracie and RansohoffXXreported on 123 faculty members at the University of Michigan with asymptomatic gallstones followed for I I to 24 years, but the study group consisted almost entirely of white American males. only 13 of the 123 subjects being female; McSherry et al" reviewed the records of 135 patients with silent gallstones, who were subscribers of the Health Insurance Plan of Greater New York and who were followed for a variable period of time (median, 46.3 months) from the date of diagnosis. In the Sirmione study a follow-up study of gallstone patients detected during the first cross-sectional study is in progress. Preliminary data after 5 years indicate a relatively high rate of development of symptoms in previously asymptomatic subjects (15.9% in 5 years); however, most symptoms were observed during the first 2 years and a much lower rate has been observed thereafter (unpublished observation). The observation that the yearly probability of the development of biliary problems appears to decrease with time was observed also in the University of Michigan study,xxwhere the risk of developing symptoms decreased from 2% per year during the first 5 years to 0.5% per year during the third 5 years of observation, and is supported in part by the report of Lund," where the majority of biliary problems, during the 5- to 20-year follow-up, occurred within the first 5 years. A possible question, arising from studies on natural history of silent stones, is if the difference in outcome of subjects with gallstone disease may possibly be related to predictive factors, either demographic or related to the characteristics of gallstones. The available studies show that neither sex and age, nor size, number, and composition of stones, nor nonvisualization of gallbladder have a clear predictive value on the development
TABLE 4. Asymptomatic Gallstone Disease: Natural History Itrc.ider~c~c Rtrrr (B)
No. Subjec,t.s
R1.fc~rrnc.r
Comfort et alxy Ralston and Smith"' Newman et al" Gracie and Ransohoff McSherry et alY' *NR: not reported. $?Median.
*'
112 14 191 123 135
Yrcrrs of' Follow-up
10-20 15-30 2-22 1 1-24 3.89t
Bilicrry Ptrirl tir~d Cornp1ic~trtroil.s
Corrrplic,trtior~s
I9 29 10 16 10.4
4.4 NR:~ NR I 2
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ET AL
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157 Hagberg B, Svernnerholm L, Thoren L: Cholelithiasis in childhood. Acta Chir Scand 123:307-3 15, 1962. Van der Linden W. Simonson N: Familial occurrence of gallstone disease. lncidence in parents of young patients. Hum Hered 23:123-127, 1973. Tesler J: Cholecystitis and cholelithiasis in identical twins. Gastroenterology 7:685-686, 1946. Kennard J: Cholelithiasis in identical twins. N Engl J Med 252:1131-1132, 1955. Laurens H: Cholelithiasis in identical twins. Gastroenterology 29:1096-1097. 1955. Harvald B, Hauge M: A catamnestic investigation of Danish twins: A preliminary report. Dan Med Bull 3:150-158, 1956. Doig RK: Illness in twins 111. Cholelithiasis Med J Aust 2:716-717, 1957. Gilat T. Feldman C , Halpern Z, et al: An increased familial frequency of gallstones. Gastroenterology 84:242-246. 1983. Barbara L, Festi D. Morselli Labate AM, et al: The Sirmione study: Familial frequency of gallstone disease. (Abstr.) Hepatology 4: 1086, 1984. Scragg RKR, McMichael AJ. Baghurst PA: Diet, alcohol and relat~veweight in gallstone disease: A case-control study. Br Med J 288:1113-1119. 1984. Knowler WC, Carraher MJ. Petitt DJ: Diabetes mellitus, obesity and cholelithiasis. In: Capocaccia L. Ricci G. Angelico F, Angelico M, Attili AF (Eds): Epidemiology and Prevention of Gallstone Disease. Lancaster, MTP Press. 1984. pp 85-9 1 . Jorgensen T: Gallstones in a Danish population. Relation to weight. physical activity, smoking. coffee consumption and diabete mellitus. Gut 30:528-534, 1989. Diehl AK. Haffner SM. Knapp JA. et al: Dietary intake and the prevalence of gallbladder disease in Mexican Americans. Gastroenterology 97: 1527-1533, 1989. Hanis CL. Ferrell RE, Tulloch BR, et al: Gallbladder disease epidemiology in Mexican Americans in Starr County. Texas. Am J Epidemiol 122:820-829. 1985. Diehl AK, Rosenthal H. Hazuda HP, et al: Socioeconomic status and the prevalence of clinical gallbladder disease. J Chron Dis 38:1019-1026, 1985. Scragg RKR. McMichael AJ. Seamark RF: Oral contraceptives, pregnancy, and endogenous oestrogen in gallstone disease. A case-control study. Br Med J 288:1795-1799, 1984. Layde PM, Vessey MP, Yeates D: Risk factors for gall-bladder disease: A cohort study of young women attending familial planning clinics. J Epidemiol Community Health 36:274-278, 1982. Royal College of General Practitioners Oral Contraception Study: Oral contraceptives and gallbladder disease. Lancet 2:957-959, 1982. Williams CN, Johnston JL, Weldon KLM: Prevalence of gallstones and gallbladder disease in Canadian Micmac Indian women. Can Med Assoc J 117:758-760, 1977. Jorgensen T: Gallstones in a Danish population: fertility period, pregnancies, and exogenous female sex hormones. Gut 29:433-439, 1988. Kern F, Everson GT, De Mark B, et al: Biliary lipids, bile acids and gallbladder function in the human female. Effect of pregnancy and the ovulatory cycle. J Clin Invest 68:12291242, 1981. Everson GT, McKinley C , Lawson M , et al: Gallbladder function in the human female: Effect of the ovulatory cycle, pregnancy and contraceptive steroids. Gastroenterology 82:711719, 1982. Sarles H, Chabert C , Pommeau Y, et al: Diet and cholesterol gallstones. A study of 101 patients with cholelithiasis compared to 101 matched controls. Am J Dig Dis 14:531-534, 1969.
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