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Intrahepatic stones: Is it a lifestyle disease?

Intrahepatic stones (IHS) may be primary when they are formed in the intrahepatic bile ducts, and secondary when they originate from the gallbladder and slip into the bile ducts. Almost 50% of patients with IHS have associated gall stones, suggesting that the IHS be secondary. While the prevalence of IHS is 0.6–1.3% in the West, it is 12% in Malaysia, 18% in Korea, 38% in China, and 47% in Taiwan. In Japan, IHS used to be common during the 1950s when the local diet was low in fat and protein, but with economic development and improvement in the quality of life its prevalence has been declining. Patients with IHS manifest with recurrent pyogenic cholangitis, associated jaundice, abdominal pain, and fever. Repeating such attacks may ultimately lead to liver abscess and secondary biliary cirrhosis, while cholangiocarcinoma may occur in 10% of patients, as reported from Japan. The primary goals of treatment in IHS, therefore, are to eliminate attacks of cholangitis and to stop the progression of liver disease. Surgery has a primary role in IHS because hepatolithiasis tends to recur. However, multiple sessions of endoscopic removal or use of a percutaneous transhepatic cholangiography (PTC) approach may be tried when surgical resection of the affected lobe is difficult. Available evidence indicates that environmental factors rather than ethnicity are responsible for causing IHS. While studies have assessed the etiological association of individual risk factors such as diet, biliary anatomy, and infections with IHS, to date no large study has established the genetic link between lifestyle risk factors and IHS. To examine such an association, Momiyama et al. report in this issue of the Journal a case–control study conducted in Taiwan, where the incidence of IHS is one of the highest in the world. They compared 151 newly diagnosed patients with two control populations. Information on lifestyle factors was collected using a self-administered questionnaire. Females with IHS were significantly shorter in height than controls. Having six or more children increased the odds ratio for IHS by 20.4 in men (95% confidence interval 1.89–221) and 2.82 (0.97–8.22) in women. Conversely, increasing level of education lowered the risk of IHS. Women who had consumed ground-surface water for a long period had a somewhat increased risk (P = 0.05). The authors concluded that lower socioeconomic status, with its concomitant increase in family size and poor hygiene, may be involved in the development of IHS. These conclusions are consistent with those of an older study which showed that malnutrition and low economic status were associated with a high incidence of IHS. Although Momiyama et al.’s case–control study was well conducted, there are certain issues which need further considerations. For example, there is no ready explanation for a link between IHS and intake of spinach and butter, as was evident from the dietary history. This is an inherent problem related to any diet-related study, wherein it is difficult for subjects to remember the diet eaten over many years, during which there may also be a lack of consistency in eating pattern. On the other hand, intake of butter may alter the intrahepatic lipid composition favoring stone formation, and use of unwashed spinach may promote parasitic infestations. The other important issue is the possible role of biliary stasis and infection in the pathogenesis of IHS. Although the aim of the study by Momiyama et al. was only to look at lifestyle risk factors, their conclusion about the relation between IHS and low socioeconomic status does point toward an infective pathogenesis. It has been thought that IHS are brown pigment (bilirubin carbonate) stones. These contain high levels of free bile acids, produced as deconjugated products of glycine and taurine bile acids by bacterial deconjugating enzymes. In the West, hepatolithiasis is mainly associated with bile stasis caused by postoperative strictures, sclerosing cholangitis, choledochal cyst, Caroli’s disease, and biliary neoplasms, whereas a high prevalence of IHS in East Asia has been believed to be related to Clonorchis (C) sinensis infection and ascariasis. Also in this issue of the Journal, Choi et al. report on their Korean study evaluating the role of C sinensis infection as a risk factor for the development of gallstones. One hundred and thirtyeight patients with gallstones (intrahepatic 44, gallbladder 67, extrahepatic 27) and appropriately matched controls underwent bile microscopy and serological tests for C sinensis using enzymelinked immunosorbent assay. In addition, radiological examinations and interviews concerning the history of eating raw freshwater fish were conducted. According to multivariate analysis, radiological evidence of C sinensis was the only risk factor for IHS. Similar reports exist about the association of biliary ascariasis with IHS. Within the biliary tree, these parasites produce inflammation of the biliary epithelium, enhancing mucin secretion and producing a nidus for stone formation with fragments of parasites and their eggs. Another issue raised by the study of Momiyama et al. is the use of appropriate radiological techniques for evaluation of IHS. The authors mention the use of ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) in making the diagnosis of HIS; however, details were not provided. Even though direct cholangiography (percutaneous or endoscopic) is the best method for evaluation of hepatolithiasis, non-invasive imaging modalities such as US, CT, and MRI accurately depict the normal anatomy and presence of IHS. Each modality has its pros and cons for informing treatment choices in a particular patient. In one study, the accuracy of combined unenhanced and contrast-enhanced helical CT and endoscopic retrograde cholangiography or PTC for diagnosis of bile duct stones was evaluated in 1090 patients. The sensitivity of combined CT for diagnosis of IHS and common bile duct stones was 73% and 71%, respectively, while corresponding specificities were 98% and 97%. Eleven of 24 (45%) cholesterol stones, 21 of 25 (84%) black pigment stones, and 15 (75%) of 21 brown pigment stones were detected on comAccepted for publication 2 June 2008.