World J. Surg. 28, 206-210, 2004DOI: 10.1007/s00268-003-6879-x O Journal of

SURGERY© 2004 by the Sociere

nationale de Chiwrgie

Surgical Globetrotting

Changing Patterns of Gallstone Disease in Korea

Yong-Hyun Park, M.D.,' Sang-Jae Park, M.D., 1 Jin-Young Jang, M.D.,' Young Joon Ahn, M.D., 1

Youn-Chan Park, M.D., 1 Yong Bum Yoon, M.D., 2 Sun-Whe Kim, M.D. 1

'Department of Surgery, Seoul National University, College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744 Seoul, Korea2Department of Internal Medicine, Seoul National University, College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744 Seoul, Korea

Published Online: January 8, 2004

Abstract. The aim of this study was to investigate the epidemiologic char-acteristics and changing patterns of gallstone disease in Korea over a re-cent 20-year period. A total of 4020 gallstone patients who had undergonesurgery at Seoul National University Hospital during 1981-2000 were ana-lyzed according to periods: period I (1981-1985: 831 cases); period II(1986-1990: 888 cases); period III (1991-1995: 1040 cases); period IV(1996-2000: 1261 cases). The literature from 13 institutes in Korea report-ing a total of 13,101 gallstone cases were reviewed to elucidate the nation-wide trend. The number of gallstone cases gradually increased. A femalepredominance was not noted (F/M = 1.17-1.37) as is seen in Western coun-tries. The patients with common bile duct (CBD) stones were older thanthose with gallbladder (GB) stones or intrahepatic duct (HID) stones. Overtime, the relative proportion of those with a GB stone increased, plateauing(80-85%) during the 1990s; that of patients with CBD stones decreased(34% —* 19%); and that of those with IHD stones remained unchanged (11-15%). Over the entire period, the rural pattern of gallstone formation (lownumber of GB stones, high numbers of CBD and IHD stones) has becomesimilar to the urban pattern. The body mass index (BMI) of the GB stonegroup was above average, as were the BMIs of the CBD stone and IHD stonegroups. Throughout the literature review, this same changing pattern ofthe relative proportion of gallstone disease was confirmed. Thus the pat-tern of gallstone disease in Korea has become similar to that seen in West-ern countries except for a high prevalence of hepatolithiasis.

The incidence and the pattern of gallstone disease vary from placeto place, attributed to the biologic environment and socioeconomicstatus [1-4]. Comparing gallstone disease in East Asia with that inWestern countries, East Asian people (e.g., Koreans, Japanese,Chinese) have a higher prevalence of pigment stones, common bileduct (CBD) stones, and intrahepatic duct (IHD) stones and lessfemale predominance [5-10]. These differences seem to be relatedto their high-carbohydrate, low-fat, low-protein diets as well as tothe high prevalence of biliary Clonorchis and Ascaris infections inEast Asia [7-10]. However, as westernization of the socioeconomicenvironment has progressed in Asia, the patterns of gallstone dis-ease have changed accordingly. In China, Zhu et al. reported thatthe ratio of persons with GB stones to those with bile duct stoneshas increased from 1.5 during the 1970s to 7.4 during the 1980s [11].

Correspondence to: Sun-Whe Kim, M.D., e-mail: sunkim@plaza.snu.ac.kr

In Japan, a high proportion of cholesterol stones and a low propor-tion of IHD stones have been reported [12]. As Koreans adoptmore westernized life styles, epidemiologic changes in gallstonedisease can be expected. Hence the aim of this study was to inves-tigate the epidemiologic characteristics and changing patterns ofgallstone disease in Korea over a recent 20-year period.

Patients and Methods

A total of 4020 gallstone patients who had been treated surgicallyfor gallstone disease at Seoul National University Hospital be-tween 1981 and 2000 were enrolled in this study. Cases involvingreoperation due to residual stone or incidental gallstone duringlaparotomy were excluded. We divided the 20-year study periodinto four segments—period 1(1981-1985), period 11 (1986-1990),period III (1991-1995), and period IV (1996-2000)—to determinethe changing epidemiologic patterns. Patients were classified intoseven subgroups and three stone groups based on the stone loca-tion (Table 1). The analytic factors of this study encompassed age,sex ratio, frequency of subgroups and stone groups, residentialarea, and degree of obesity using the body mass index. In addition,the data from 13 institutes in Korea, reporting a total of 13,101gallstone cases during the study period, were reviewed to elucidatenationwide trends of relative incidences of the gallstone diseaseaccording to the gallstone groups [13-26].

The values determined for the four groups were compared byStudent's t-test test or the 2 test. Correlations between factorswere tested with Pearson's linear function. SPSS 10.0 (SPSS, Chi-cago, IL, USA) was used for the analysis. Ap value of < 0.05 wasconsidered significant.

Results

Case Number, Age, and Sex Ratio

The number of gallstone surgery cases gradually increased over thestudy's 20 years at Seoul National University Hospital (p = 0.031)(Table 2). The female/male ratio ranged from 1.15 to 1.37 over the

Park et al.: Gallstone Disease Patterns in Korea 207

Table 1. Classification of groups according to the location of stones.

Seven subgroups1: GB2: GB + CBD3: CBD4: GB + CBD + IHD5: IHD + GB6: IHD + CBD7: IHD

Three stone groupsGB stone groups: 1, 2, 4, 5CBD stone groups: 2, 3, 4, 6IHD stone groups: 4, 5, 6, 7

GB: gallbladder; CBD: common bile duct; IHD: intrahepatic bile duct.

study period but seemed substantially unchanged. Patients becamemore or less older throughout the study period (p = 0.081).

Frequency of Gallstone Groups

The frequency of GB stones gradually increased from 81% duringperiod Ito 85.7% during period III (p = 0.007) and then slightlydecreased to 82.9% during period IV (p = 0.076). The frequency ofCBD stones during period I was 34.1%, which decreased graduallyto 18.9% during period IV (p < 0.001). The frequency of IHDstones was 10% to 15% and remained unchanged throughout thefollowing periods (p = 0.344). The sex ratio of the GB stone groupand the IHD stone group showed a slight female predominanceover the study period (Table 3), although no difference betweenthe sexes was observed in the CBD stone group (p = 0.193).

Relation between Area of Residence and Stone Location

Considering the relation between the patients' residence and stonelocation, we found that during period I the relative frequency of GBstones in urban areas (67%) was much higher than that in ruralareas (44.7%) (p < 0.001). In contrast, the relative frequencies ofCBD stones and IHD stones in rural areas (35.9% and 19.3%, re-spectively) were higher than those in the urban areas (24.7% and8.3%, respectively) (p < 0.001) (Fig. 1). However, this differencenarrowed as the frequency of GB stones increased and the frequen-cies of CBD and IHD stones decreased in the rural area during the1990s.

Frequency and Mean Age of Subgroups

We then examined subgroups of patients: those with GB stonesonly, CBD stones only, IHD stones only, GB+CBD stones,GB+IHD stones, CBD+IHD stones, and GB+CBD+IHDstones. The frequency of GB stones only gradually increased, from61.9% during the early 1980s to 73.4% during the late 1990s (p =0.041). The frequencies of GB+CBD stones (p = 0.012) and ofCBD stones only (p = 0.015) have decreased continuously overtime. Finally, the frequencies of CBD+IHD stones (p = 0.780) andIHD stones only (p = 0.258) remained constant over the study pe-riod (Table 4).

The mean age of each subgroup showed a slightly increasing ten-dency over the study period. During the early 1980s, theCBD+IHD stone subgroup and the IHD stone-only subgroup pa-tients were 7 to 11 years younger than the GB stone-only subgroup,

Table 2. Total number, sex ratio, and mean age of patients according tothe time periods.

Period I Period II Period III Period IVParameter (1981-1985) (1986-1990) (1991-1995) (1996-2000)

No. of cases 831 888 1040 1261Sex ratio 1.25 1.37 1.28 1.17

(F:M)Mean age 51.4 53.2 53.3 54.0

(years)

but during the 1990s this difference had decreased. During the1990s, however, the GB+ CBD stone subgroup (p < 0.001) and theCBD stone-only subgroup patients (p < 0.001) became older thanthe GB stone-only subgroup (Fig. 2).

Body Mass Index in the Stone Groups

We determined the body mass index (BMI) of the stone group pa-tients to examine the relation between the degree of obesity andgallstone location. The BMI (Quetelet index, in kilograms persquare meter) of all stone groups increased over the study period (p< 0.001). The BMI of the GB stone group was always above aver-age and higher than those of the CBD stone group and the IHDstone group throughout the study period (Fig. 3).

Chronologic Change of Gallstone Location in Korea

(Literature Review of 13,101 Cases)

To confirm the nationwide trends and demographics of gallstonesin Korea, we collated data for 13,101 cases from 13 Korean insti-tutes for the years between 1960s and the 1990s The GB stonegroup accounted for about 50% of cases during the early 1960s, afigure that gradually increased to 85% during the late 1990s. Thefrequency of CBD stones decreased from 68% during the early1960s to 20% during the late 1990s; and the frequency of IHDstones remained almost stationary, in the range of 15% to 20%,throughout this 40-year period (Fig. 4).

Discussion

The patients enrolled in this study were diagnosed as having gall-stone disease after surgery; therefore it is not accurate to say thatthis study represents or reflects the findings of a study based onnationwide epidemiologic data. However, it does involve a largeamount of data collected over 20 years at the same institute, andour data might reflect epidemiologic changes in the pattern of gall-stone disease in Korea.

The present study indicates that the number of gallstone patientsoperated on has increased over these 20 years. As previously men-tioned, this does not mean that the prevalence of gallstone has beenincreasing in Korea. In the United States the prevalence of gall-stones in adults ranged from 10% to 15% and increased with age[27]. In Korea, few studies have been undertaken regarding the in-cidence and prevalence of gallstones, but several studies have re-ported that the prevalence of gallstone disease was 2.0% to 4.2%[28, 29].

The gallstone patients in our study were divided into seven sub-groups and three stone groups. Over the 20 years of this study, the

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World J. Surg. Vol. 28, No. 2, February 2004

Table 3. Relative frequency of each stone group according to the location of the stone for four time periods."

Location of stone

Condition GB group CBD group IHD group No. of total cases (%)

Male 290/310/381/493 140/119/133/120 50/49/56/60 369/375/457/581 (44.4/42.2/43.9/46.1)Female 383/413/510/552 143/149/114/118 58/85/65/105 462/513/583/680 (55.6/57.8/56.1/53.9)Total no. 673/723/891/1,045 283/268/247/238 108/134/121/165 831/888/1,040/1261 (100/100/100/100)Total % 81.0/81.4/85.7/82.9 34.1/30.2/23.8/18.9 13.0/15.1/11.6/13.1

Some patients overlap in the stone groups."1981-1985/1986-1990/1991-1995/1996-2000

Fig. 1. Relation between location of stones and the patients' area of resi-dence. GB*: gallbladder; group; CBDt: common bile duct; IHD$: intrahe-patic bile duct.

Table 4. Relative frequency and ution of patients according to timeperiod subgroups."

Subgroup Relative frequency (%) Age (years), mean

GB 61.9/63.9/72.0/73.4 51.5/51.2/52.1/52.9GB + CBD 14.8/12.7/11.3/8.2 55.5/61.6/60.0/59.8CBD 10.3/8.6/5.0/5.2 51.7/56.4/57.8/61.8GB + CBD + IHD 3.5/4.1/1.6/1.0 50.8/55.4/54.2/58.6GB + IHD 0.8/1.0/0.7/0.1 41.3/51.2/54.7/52.0IHD + CBD 5.4/4.8/5.8/5.3 44.7/49.2/53.7/51.8IHD 3.2/5.1/3.6/6.7 40.5/41.5/47.5/51.5

"1981-1985/1986-1990/1991-1995/1996-2000.

relative incidence of the gallbladder stone group has increasedfrom 81% during the early 1980s to 85.7% during the early 1990s;this figure then decreased somewhat to 82.7% during the late1990s. The major cause of this decrease was the decreased numberof GB+CBD subgroup patients, whereas the incidence of thosewith GB stones only continues to increase. The primary reason theincidence of GB stone-only patients undergoing surgery has beenincreasing, especially during the 1990s, is routine medical checkups[28], which includes ultrasonography. Therefore the number ofmildly symptomatic gallstone patients has increased. In addition,laparoscopic cholecystectomy became popular in Korea during the1990s, which has made it easier for physicians and patients to agreeto cholecystectomy. However, as mentioned previously, the in-creased number of operations does not mean an increased inci-dence of GB stone disease.

The incidence and relative increase in the surgical CBD stonegroup has continuously diminished over the 20 years of the study.The possible causes are as follows: (1) Most CBD stone cases origi-

Fig. 2. Age distribution of subgroups. 0: GB; q : GB + CBD; L:CBD A: 1HD; K: 1 HD + CBD

Fig. 3. Comparison of Quetelet index between the stone groups. *AverageQuetelet index for men during 1985 was 21.8. * *Average for women during1985 was 20.9. tAverage for men during 1995 was 22.6. Average for womenduring 1995 was 21.7.

nate from GB stones, so the incidence of CBD stones decreaseswith the increased number of cholecystectomies. In this study, thefact that CBD stone patients were 4 to 10 years older than GBstone-only patients may reflect the time needed for the stone tomigrate naturally from being a GB stone to becoming a CBD stone.(2) Therapeutic endoscopy was introduced into Korea during theearly 1980s, and endoscopic choledocholithotomy has now becomethe treatment of choice for CBD stones. Therefore the incidence of

Park et al.: Gallstone Disease Patterns in Korea 209

100

80

60

40

20

0'61-65 '66-70 '71-75 '76-80 '81-85 '86-90 '91-95 '96-00

Fig. 4. Chronologic changes in the relative frequency of gallstone groupsin Korea. N: GB stone group; A: CBD stone group; S: 1HD stone group.

surgical cases has markedly decreased. (3) As the socioeconomicand environmental conditions have improved and the risk factorsfor pigment stones (e.g., high-carbohydrate, low-fat, low-proteindiet, bile duct infection, poor hygiene) have been removed, the in-cidence of pigment CBD stones has decreased. When we comparedEngel's coefficient, which represents the socioeconomic status ofthe nation, with the frequency of CBD stones, we found that theprevalence of CBD stones was strongly correlated with Engel's co-efficient (Fig. 5) (r = 0.983, p < 0.001). In the future, as laparo-scopic cholecystectomy and interventional endoscopy becomemore popular, and the socioeconomic and environmental condi-tions improve, the surgical incidence of CBD stone is expected todecrease even more.We could not see any specific trend for theproportion of IHD stones in Korea. The causes of IHD stones areknown to be a high-carbohydrate, low-fat, low-protein diet and abiliary infection such as clonorchiasis or ascariasis [12, 30, 31].Hepatolithiasis is thought to be more common in East Asia than inWestern countries; however, in China and especially in Japan theincidence of IHD stones has decreased to less than 5% [11, 12]. Incontrast, although the life style, including dietary habits and theenvironment, has become increasingly westernized in Korea [32],the incidence of IHD stones has been sustained. Possible causes ofthis phenomenon are as follows: First, some known risk factors forIHD stones (clonorchiasis and Oriental dietary habits) still exist inKorea. In reports from institutes in southwestern Korea, the inci-dence of hepatolithiasis is still higher than in other areas, which wasthought to be related to the clonorchiasis [33]. It is certain that thedietary habits of Koreans are shifting toward the Western style, al-though traditional dietary habits still comprise an important part ofdietary intake; for example, rice is the most important staple foodin Korean. The second possible cause involves genetic factors fa-voring hepatolithiasis, which may exist in Korean people. This pos-sible genetic tendency has been reported in some studies [34, 35].

The mean age of Korean gallstone patients increased steadilyover the study period. During the early 1980s, the mean age of IHDstone patients was 7 to 11 years younger than that of the GB stonepatients; this trend weakened during the 1990s, when CBD stonepatients became 5 to 9 years older than GB stone patients. MostCBD stones originate from GB stones, and it may take several yearsfor a GB stone to migrate into the CBD. The younger age of thepatients with IHD stones compared to those with GB or CBD

70

60ova

50

40

30

20

10

061-65 66-70 '71-75 '76-80 '81-85 '86-90 '91-95 '96-00

Fig. 5. Relation between Engle's coefficient (co.) and the relative fre-quency of the CBD stone group over the entire study period. Circles: CBDstones; triangles: Engel's coefficient.

stones suggests that IHD stones may either develop or cause symp-toms at an earlier stage [12].

Women are predisposed to gallstone disease by two- to threefoldin Western countries, and it has been reported that oral contracep-tives are related to this female predominance [36, 37]. In the pre-sent study in Korea, the female/male ratio was 1.17 to 1.37. Possiblecauses of the lower female predominance regarding Korean gall-stone disease are as follows. (1) There is a relatively high preva-lence of CBD and IHD stones, which shows relatively less femalepredominance than among those with GB stones. In Japan, femalepredominance of gallstone disease was found to be weak during the1960s [5]. However, as the proportion of cholesterol stones in-creased, the sex ratio pattern became similar to that found in theWest [12]. (2) Even though the actual prevalence of gallstone dis-ease is higher in women, there may be fewer female than male in-patients and surgical patients. This is because men undergo medi-cal checkups more often than women in Korea, at a ratio 1.5:1.0 [28,29]. Unfortunately, housewives, who are at highest risk of gallstonedisease, do not go to the hospital until they experience serioussymptoms.

Obesity is known to increase the likelihood of gallbladder stones,especially cholesterol stones [38]. As Koreans are becoming moreobese because they are adopting high-calorie diets, cholesterolgallstone disease is expected to increase in the future.

Conclusions

Although our data are from a single hospital-based epidemiologicstudy, when we consider similar results from a review of the Koreanliterature, we conclude that the frequency of GB stones has gradu-ally increased and that of CBD stones has decreased, which isclosely related to the socioeconomic status of the nation. However,the frequency of IHD stones remains unchanged in Korea. Thispersistent, relatively high frequency of IHD stones in Korea, giventhe westernization of the diet, is a highly significant finding. Studieson the developmental mechanism and the proper treatment ofIHD stones in Koreans should be conducted.

Resume. Le but de cette etude a ete de determiner les caracteristiquesepidemiologiques et leurs eventuels aspects evolutifs de la maladie

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lithiasique en Coree pendant les 20 dernieres annees. On a analyse lesdossiers de 4020 patients presentant une lithiase it I'Hopital NationalUniversitaire de Seoul (1981-2000) pendant plusieurs periodes differentes:periode I 1981-1985: 831 cas), periode 11 (1986-1990: 888 cas), periode III(1991-1995: 1040 cas) et periode IV (1996-2000: 1261 cas). La litteratureprovenant de 13 institutions en Coree rapportant 13101 cas de lithiase a eterevue pour elucider Ia tendance nationale. Le nombre de cas de lithiase aaugmente. Comme dans les pays Occidentaux, on a note une predominancefeminine (F/M = 1.17-1.37). Les patients ayant une lithiase de la voiebiliaire principale (VBP) etait plus ages que les patients ayant une lithiasebiliaire simple ou les patients ayant une lithiase intrahepatique (LIH).Avec le temps, la proportion relative de patients ayant une lithiasevesiculaire a augmente pour atteindre un plateau (80-85 %) dans lesannees 1990, Ia proportion de patients porteur de lithiase de la VBPa diminue (34% - 19%) et le groupe de patients porteurs de LIH estrestee inchangee (11-15%). De meme, le site de la lithiase (bas, haut,intrahepatique) dans la population rurale s'est rapproche de ce que Ponobserve en ville. L'indexe de masse corporelle dans le groupe porteur delithiase vesiculaire etait plus eleve que la moyenne, et plus eleve que celuides patients porteur de lithiase de la VBP ou de LIH. A travers une revue dela litterature, cette meme tendance s'est confirmee en ce qui concerne laproportion relative de patients porteurs de maladie lithiasique. Lestendances de la maladie lithiasique en Coree sont devenues similaires acelles des pays occidentaux sauf en ce qui concerne la prevalence elevee delithiase intrahepatique.

Resumen. Investigar Ia evoluciSn de las caracteristicas epidemiol6gicas dela litiasis biliar a to largo de los Gltimos 20 anos en Corea. Se analizaron4020 pacientes con litiasis biliar tratados quirbrgicamente en el HospitalNational Universitario de Seoul. Se dividieron, de acuerdo con diferentesperiodos de tiempo: periodo I (1981-1985; n = 831), periodo II (1986-1990;n = 888) periodo III (1991-1995, n = 1,040) y periodo IV (1996-2000;n = 1,261). Ademas, se revisaron 13,101 casos de litiasis biliar de 13Instituciones Hospitalarias de Corea, con objeto de averiguar la tendenciade esta enfermedad a escala nacional. La incidencia de Ia litiasis biliar seha incrementando paulatinamente; sin embargo, no se constatd unapredominancia por el sexo femenino (M/V = 1.77-1.37) como ocurre enpaises occidentales. Los pacientes con coledocolitiasis (CBD) eran masviejos que los que aquejaban una colelitiasis (GB) o una hepatolitiasis(DID). A to largo del tiempo, los pacientes con GB aumentaron hastaalcanzar una meseta (80-85%) en los anos noventa. La coledocolitiasisdisminuyb (34% -* 19%) y la hepatolitiasis no se modifico (11-15%).A lolargo de estos 20 anos, las caracteristicas de la litiasis biliar en zonasrurales (escasos casos de GB y muchos de CBD y IHD) se fue equiparandoa los de las ciudades. El indice de masa corporal era superior en pacientescon GB que en los que presentaron una CBD o HID. Nuestras observacionescoinciden con las referidas en la literatura mundial at respecto. Lascaracteristicas de la litiasis biliar en Corea son semejantes alas observadas enlos paises occidentales, excepto por to que a la alta incidencia de hepatolitiasis(IHD) se refiere.

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