This prospective study was conducted in 26 secondary and tertiary hospitals in South Korea from March to April 2005. Subjects included consecutive patients with gastrointestinal symptoms who were admitted to the Department of Internal Medicine during the study period. Gastrointestinal symptoms were defined as the presence of any of the following: nausea, vomiting, diarrhea, constipation, abdominal pain, heartburn, dyspepsia, jaundice, indigestion, and fecal incontinence. Patients were excluded if they had been admitted with non-gastrointestinal symptoms, admitted more than twice during the study period, unable to give a thorough history, < 14 years old, and declined to participate in this study.

The institutional review board of each participating hospital approved this study. Informed consent for participation in this study was obtained from each patient included in the study.

Upon admission, attending physicians filled out a structured questionnaire for each subject after a medical interview. The questionnaire included the following information: rivers nearest to the birthplace or place of current residence in order of decreasing duration, history of eating raw freshwater fish and/or shellfish, including the time, place and species of the fish and/or shellfish consumed, past history of clonorchiasis and treatment including type and duration, and past history of hepatobiliary diseases. Rivers nearest to the birthplace or place of current residence included 10 major rivers in South Korea: Nakdong, South Han, North Han, Geum, Yeongsan, Seomjin, Mangyong-Dongjin, Hyeongsan, Bulyeong-Wangpi, and Namdae-Yeongok-Osip.

The questionnaire also included close-ended questions such as: (1) did you (the patient him/herself) know that clonorchiasis can be acquired by ingesting raw freshwater fish? (2) Did you know that clonorchiasis can also be acquired by eating freshwater shellfish? (3) Did you know that clonorchiasis can be transmitted via kitchen knives and/or towels? (4) Did you know clonorchiasis can be transmitted by unwashed hands of raw freshwater fish handlers? (5) Did you know clonorchiasis can be prevented by eating fully cooked freshwater fish?

After admission, all the patients underwent laboratory tests, which included complete blood count with differential count, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and total bilirubin. When transabdominal US or abdominal CT was done after admission or within 6 mo of admission, presence of dilatation of the intrahepatic bile ducts and/or extrahepatic bile duct was recorded.

Diagnosis of clonorchiasis was based on the presence of one or more of the following findings: (1) detection of C. sinensis eggs, metacercariae, or adult worms in stools collected during admission; (2) presence of induration with area of 60 mm² or greater on the forearm after skin test with an intradermal injection of diluted crude antigen of C. sinensis; (3) positive for serum antibodies to C. sinensis using ELISA; (4) detection of C. sinensis eggs, metacercariae, or adult worms in bile collected during percutaneous transhepatic biliary drainage or endoscopic nasobiliary drainage; (5) finding of diffuse dilatation of intrahepatic bile ducts in transabdominal US, abdominal CT, or cholangiography; and (6) detection of C. sinensis infection in stools or bile examination, and/or presence of positive intradermal test described in medical records. To investigate the possible association between clonorchiasis and hepatobiliary diseases, medical records of each patient were reviewed for diagnosis of the following diseases: cholangitis, choledocholithiasis, gallbladder stones, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, biliary pancreatitis, and alcoholic pancreatitis.

Overall infection rate of C. sinensis and that according to the river basins were calculated. Infection rates between raw freshwater fish and/or shellfish eaters and non-eaters were also compared. Level of knowledge on transmission and prevention of clonorchiasis was assessed. By using the χ² test and independent t test, the differences between infected and non-infected patients were assessed with regard to the presence of peripheral eosinophilia and abnormal liver function tests. Sensitivities of various diagnostic methods used in this study were evaluated.

Association with hepatobiliary diseases was evaluated for infected and non-infected patients by using the χ² test. Association between clonorchiasis and cholangiocarcinoma among raw freshwater fish and/or shellfish eaters from high prevalence river basins (Nakdong, Yeongsan, Seomjin, and Hyeongsan Rivers) and lower prevalence river basins (the remainder) was assessed using the t test and odds ratio. After correction for regions, Cochran’s Mantel-Haenszel χ² test was used to evaluate the association between clonorchiasis and cholangiocarcinoma. SPSS (version 12.0 for Windows; Chicago, IL, USA) was used for statistical analysis and P < 0.05 was considered statistically significant.

Subjects included 3080 patients from 26 hospitals. Number of patients according to rivers nearest to the birthplace or place of current residence was 947 (31.5%) in Nakdong, 774 (25.7%) in South Han, 270 (9.0%) in North Han, 303 (10.1%) in Geum, 137 (4.6%) in Yeongsan, 97 (3.2%) in Seomjin, 266 (8.8%) in Mangyong-Dongjin, 154 (4.8%) in Hyeongsan, six (0.2%) in Bulyeong-Wangpi, 64 (2.1%) in Namdae-Yeongok-Osip Rivers and 71 unanswered (Table 1). There were 1953 male and 1127 female patients. Male to female ratio was 1.7:1. Mean age of the patients was 58.2 years old (range, 14-98).

The number of patients with past history of raw freshwater fish and/or shellfish ingestion was 1140 (37.3%) out of 3055 of those who answered the questionnaire, while there were 191 (62.7%) patients with no past history of ingestion, and there were 25 unanswered questionnaires. Of those with a past history of ingestion, 156 out of 1140 patients (13.9%) ingested only once, 318 patients (28.3%) two to four times, and 648 patients (57.8%) more than five times. Initial time of raw freshwater fish and/or shellfish ingestion was within 10 years in 278 patients (25.5%), 11-20 years ago in 207 (19.0%), 21–30 years ago in 179 (16.4%), > 30 years ago in 427 (39.1%), and 49 questionnaires were unanswered (Table 2).

In 1140 patients with a past history of ingestion, river basins nearest to the place of ingestion were Nakdong for 394 patients (35.2%), South Han for 156 (13.9%), North Han for 207 (18.5%), Geum for 84 (7.5%), Yeongsan for 47 (4.2%), Seomjin for 65 (5.8%), Mangyong-Dongjin for 78 (7.0%), Hyeongsan for 54 (4.8%), Bulyeong-Wangpi for three (0.3%), Namdae-Yeongok-Osip Rivers for 32 (2.9%), and 20 questionnaires were unanswered (Table 3).

Only 150 (5.0%) patients had been diagnosed with clonorchiasis in the past. The number of patients without a past history of diagnosis or treatment was 2880 (95.0%) and 50 questionnaires were unanswered. Of those 150 patients with a past history of clonorchiasis, 120 (81.6%) had received eradication therapy, 14 (9.5%) did not receive any therapy, 13 (8.8%) had undergone treatment without definite diagnosis, and three did not answer. There were 657 patients (21.3%) with a past history of hepato-biliary diseases. Of these patients, 395 (60.4%) had bile duct stones, 118 (18.1%) cholangitis, 64 (9.6%) cholangiocarcinoma, 116 (17.6%) jaundice of uncertain cause, and 112 (16.5%) pancreatitis.

Of 3049 patients who answered the questionnaire, 2464 (80.8%) knew that clonorchiasis can be acquired by ingesting raw freshwater fish and 1629 (53.3%) knew that clonorchiasis can also be acquired by eating raw freshwater shellfish. Also, 1141 (47.2%) knew that clonorchiasis can be transmitted via kitchen knives and/or towels and 1192 (39.1%) acknowledged that clonorchiasis can be transmitted by unwashed hands of raw freshwater fish handlers. In addition, 2371 patients (77.8%) knew that clonorchiasis can be prevented by eating fully cooked freshwater fish (Table 4).

Diagnosis of infection: Of 3080 patients admitted to the Department of Internal Medicine during the study period, 396 (12.9%) had been diagnosed with clonorchiasis. Stool examination was positive for C. sinensis eggs, metacercariae, or adult worms in 55 patients. Intradermal test was positive in 225 patients and serum antibodies to C. sinensis using an ELISA were positive in 157 patients. In 14 patients, C. sinensis eggs, metacercariae, or adult worms were detected in bile collected during percutaneous transhepatic biliary drainage or endoscopic nasobiliary drainage. Diffuse dilatation of intrahepatic bile ducts in transabdominal US, abdominal CT, or cholangiography was found in 34 patients. C. sinensis infection in stools or bile examination and/or presence of positive intradermal test was described in the medical records of 150 patients.

Sensitivities of the diagnostic tests were highest for intradermal test (74.5%) and second highest for serum antibodies to C. sinensis using an ELISA (43.4%) (Table 5).

Among patients with clonorchiasis, there was no patient younger than 19 year old. There were seven patients (6.5%) out of 107 in their twenties, 25 (11.3%) out of 222 in their thirties, 79 (17.1%) out 463 in their forties, 99 (14.2%) out of 695 in their fifties, 113 (13.6%) out of 831 in their sixties, and 61 (10.6%) out of 575 in their seventies. There were 12 (7.5%) out of 161 patients older than 80 years (Table 6).

Distribution of infected patients according to river basins from where ingested raw freshwater fishes originated: Of 1140 patients with a history of raw freshwater fish and/or shellfish ingestion, 238 (20.9%) had been diagnosed with clonorchiasis. Also, there was evidence of clonorchiasis in 157 out of 1940 patients (6.5%) who had no history of ingestion or had not answered the questionnaire (Table 7).

Of 1120 patients who answered, the river basin nearest to the place of raw freshwater fish or shellfish ingestion was Nakdong for 132 patients, South Han for 12 patients, North Han for 15 patients, Geum for seven patients, Yeongsan for 19 patients, Seomjin for 14 patients, Mangyong-Dongjin for 10 patients, Hyeongsan for 24 patients, Bulyeong-Wangpi for none, and Namdae-Yeongok-Osip Rivers for four patients (Table 4). The river basin with highest infection rate was Hyeongsan (44.4%). Other river basins in decreasing order of infection rate were Yeongsan (40.4%) and Nakdong (33.5%).

Laboratory findings: Eosinophilia in the peripheral blood (> 400/mm³) was found in 65 of 389 patients with clonorchiasis (16.7%), while it was found in 250 of 2617 patients (9.6%) without clonorchiasis (P = 0.000) (Table 8). Serum alkaline phosphatase was 304.8 ± 418.35 U/L in 382 patients with clonorchiasis, but 234.4 ± 350.81 U/L in 2611 patients without clonorchiasis

(P = 0.002). However, levels of AST, ALT, GGT, and total bilirubin were not significantly different between the two groups (Table 8).

Association between clonorchiasis and hepato-biliary diseases: When prevalence of various hepatobiliary diseases was evaluated between patients with and without clonorchiasis, a statistically significant difference was found only for cholangiocarcinoma [34 (8.6%) vs 145 (5.4%), P = 0.015] (Figure 1A). There was no significant difference regarding cholangitis, bile duct stones, hepatitis, hepatocellular carcinoma, gallstone pancreatitis, and gallbladder cancer between patients with and without clonorchiasis (Table 9).

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Flowchart for the comparison of the frequency of cholangiocarcinoma. A: According to the presence or absence of clonorchiasis; B: According to the place of residence.

Patients were divided into two groups according to regions of the river basins nearest to the place of residence, and analyzed for association between presence of clonorchiasis and cholangiocarcinoma. Rivers of the southern region of the Korean Peninsula included Nakdong, Yeongsan, Seomjin and Hyeongsan Rivers and those of the middle region included South Han, North Han, Geum, Bulyeong-Wangpi, Namdae-Yeongok-Osip, and Mangyong-Dongjin Rivers (Figure 2). Clonorchiasis was present in 189 of 560 patients (33.8%) from the southern region, but in only 48 of 560 patients (8.6%) from the middle region (P = 0.000). While cholangiocarcinoma was found in 39 of 560 patients (7.0%) from the southern region, it was found in 19 of 560 patients (3.4%) from the middle region (P = 0.007) (Figure 1B).

Open in New Tab   Full Size Figure   Download Figure

Figure 2 Rivers in South Korea. The basins of rives are divided into middle and southern regions.

In both southern and middle region groups, there was a significant association between presence of clonorchiasis and cholangiocarcinoma [P = 0.005, odds ratio: 4.136 (95% CI, 1.422-12.030] and P = 0.040, odds ratio: 1.961 (95% CI, 1.020-3.773), respectively]. Even after correction for regional influence, there was a significant association between presence of clonorchiasis and cholangiocarcinoma [P = 0.003, common odds ratio: 2.289 (95% CI, 1.297-4.038)] (Table 10, Figure 1B).

Twenty-four of 34 patients with clonorchiasis and cholangiocarcinoma had a history of raw freshwater fish and/or shellfish ingestion. Fifteen of these patients (62.5%) had ingested raw freshwater fish and/or shellfish 30 years ago, seven patients did so within last 10 years, and the other two patients ingested raw freshwater fish and/or shellfish between 21 and 30 years ago.

Clonorchiasis is an infection caused by the parasite C. sinensis, and has been one of the most important endemic diseases in eastern Asia. Clonorchiasis can cause a variety of gastrointestinal diseases such as bile duct obstruction, acute cholangitis, hepatolithiasis, and cholangiocarcinoma.

Important areas in the research field related to this article are development of more rapid and convenient diagnostic modalities and antihelminthic vaccines, and investigation of mechanisms by which C. sinensis causes cellular injury.

Despite public efforts and education, clonorchiasis is still present in the Korean population, and more so in certain regions of the country. Also, clonorchiasis is associated with cholangiocarcinoma and is a risk factor for cholangiocarcinoma.

To prevent clonorchiasis and cholangiocarcinoma associated with this parasite infection, there is a need for public education to prevent further raw freshwater fish or shellfish ingestion.

Acute cholangitis is inflammation of bile duct that can cause fever, abdominal pain and abnormal blood test results. Hepatolithiasis refers to stone formation inside the liver. Cholangiocarcinoma is a certain type of liver cancer that originates from bile duct.

This study showed an impressive epidemiology and way of infection of clornochiasis in riverside populations of Korea. The authors collected data from 26 hospitals in only 1 mo. This is an important contribution to the etiology of cholangiocarcionoma in this part of the world. Also, the results of this study can serve as a basis for public health initiatives for prevention and mass treatment of clonorchiasis.