REVIEW ARTICLE Annals of Cancer Research and Therapy Significance of cholangiography for ESWL and gallstone dissolution therapy Tetsuo Morishita・Akitaka Eimoto・Kentaro Ohba・Masahiko Hirokawa・ Hiromi Iwahashi・Soichiro Terada*1), Hiromasa Ishii*2) Ann Cancer Res Ther 7 (2): 71-76, 1998/Received 21 Dec 1998 Key words: cholangiography, cholecystography In recent years, the use of abdominal computed tomo- reviewed, to study their roles in the period of ESWL and graphy (CT) and abdominal ultrasonography (US) has gallstone dissolution therapy. rapidly become a widely used method for diagnosis of liver, biliary tract, and pancreatic diseases1,2). CT and US History of cholangiography are non-operative examination procedures, and can out- line a target organ in either the presence or absence of There are many methods or modified methods of jaundice. CT can vividly reveal the relative position of cholangiography. Cholangiography is broadly divided organs, while US can also be applied in particular to into indirect methods including OC and rectal cholecysto- pregnant women and persons with allergies to contrast graphy (RC), IVC and DIC, and direct methods includ- agents. However, diagnosis by US is influenced by the ing endoscopic retrograde cholangiopancreatography skill level of the operators, and has some disadvantages, (ERCP) and percutaneous transhepatic colangiography for example, gas in the gastrointestinal tract or fat tissue (PTC). in an obese body induces a poor image. After the discovery of X-rays by Rontgen in 1895 Extracorporeal shock wave lithotripsy (ESWL) and followed by the report on the excretion of phenoltetrach- gallstone dissolution with oral bile acid therapy have lorophthalein in the bile by Abel and Rowntree4) in 1909, been applied to the traditional system for treatment of Graham et al.5) succeeded in performing cholangiography cholelithiasis resulting in a great change in the treatment3). in men by means of calcium tetra-bromophenolphthalein For the application of the treatments it is important to in 1924. Furthermore, in Japan, Yukio Terauchi reported ascertain sufficient excretion of the dissolving agents from his original study of cholangiography in 19256). As will be the liver into the bile ducts, their exposure to the stones of outlined later, during the period between 1940 and 1956, cholesterol and contraction of the gallbladder, as well as oral contrast agents such as iodoalphionic acid (Per- the number, size and location of the stones, especially the iodax) , iopanoic acid (Telepaque), and iophenoxic acid positional relationship to the cystic duct. For exffective (Teridax), and an intravenous contrast agent, methylg- treatment it is essential to know in advance the functional lucamine iosipamide (Biligrafin) were developed and level of the liver and biliary tract, production and flow used widely. rate of the bile. In that respect, indirect cholangiography Cholangiography has been used in Japan since 1952 . can yield more information than does CT or US. On the other hand, direct cholangiography is thought to In this paper, the significance and mechanism of in- have been first carried out by percutaneous puncture into direct cholangiography including oral (OC), intravenous the gallbladder in human beings by Bruckhardt et al.7) in (IVC) and drip infusion cholangiography (DIC) are re- 1921. This method expanded to ERCP and PTC1,8-10. The mechanism of indirect cholangiographies *1) Departments of Internal Medicine and Gastroenterology 、Shizuoka Red Cross Hospital*2) D epartment of Internal Medicine, School of Medicine, Keio University Oral cholecystography Correspondence to: Tetsuo Morishita, Department of Internal Medi- The oral contrast agents currently used include Telepa- cine, Shizuoka Red Cross Hospital, 8-2 Ohtemachi, Shizuoka-Shi, Shizuoka 420-0853, Japan que, sodium ipodate (Biloptin), isobenzamic acid (Osbil), Significance of cholangiography for ESWL and gallstone dissolution therapy 71 sodium tyropanoate (Tyropaque). Telepaque was recovered from human stools and 85% was The contrast agent, Telepaque, administered orally is excreted in cat's feces during five days after administra- quickly dissolved and absorbed by the intestine because it tion25). It has also been reported that 15% and 35% of the is liposoluble in the presence of bile acid and is absorbed administered Telepaque was excreted in human urine and by passive diffusion. In animal experiments, the agent was cat's urine, respectively25). Most of the Telepaque excreted absorbed by the entire intestinal tract including the small in the urine is conjugated with glucuronic acid, and the and large intestines11,12).As to the route of absorption, the mechanism of the urinary excretion seems to involve agent is absorbed through the portal vein system rather primarily reverse diffusion of the conjugated agent from than the intestinal lymph system12,13).However, in the case the liver into the blood. of an unstirred aqueous layer or of an insufficient micelle of bile acid, a contrast agent with high polarity should be Intravenous cholangiography easily absorbed14). At least 97% of the agent is bound to The point of the greatest difference between an intra- albumin in the blood15), which increases the water solubil- venous contrast agent and an oral contrast agent is that ity of the agent and suppresses its diffusion to other blood the former is not absorbed by the intestinal tract. Immedi- components. The binding also inhibits glomerular filtra- ately after intravenous administration, the contrast agent tion in the kidney and renal tubule secretions16). is bound to serum protein26). An experiment involving The mechanism of hepatic uptake of the contrast agent Sephadex-gel filtration of a mixture of Biligrafin and seems to involve the binding to hepatic cytoplasmic serum, the contrast agent showed three peaks in accor- protein fractions, Y (ligandin) and Z17), and "membrane dance with the protein fractions. Biligrafin seems to bind carrier mediated processes"18). The hepatic uptake seems to every protein in the serum27). The binding rates of to be due to equilibria among the degree of the binding to Biligrafin, iotroxic acid (Biliscopin), ioglycamic acid serum albumin, to Y and Z protein fractions and to (Bilivistan) and iodoxamic acid (Cholegrafin) to serum membrane carriers. In the liver the contrast agent is protein were 97%, 92%, 91%, and 86%, respectively, with conjugated with glucuronic acid by glucuronil transferase, the blood concentration of the contrast agents at 2.6× which is a microsomal enzyme19). This conjugation 10-4M28). Within 72 hours after intravenous administra- enhances the transport of the contrast agent from Disse's tion of Biliscopin, Biligrafin, and Cholegrafin to rats, spaces to the hepatocytes by means of a concentration more than 90% of the agents were excreted in the feces, gradient. The conjugated contrast agent is excreted into regardless of their doses. In the urine, 8-30% of each agent the bile, to which the active carrier-mediated process and is excreted in proportion to its dose20). Urinary excretion the optimal size of a molecule of the converted contrast of contrast agents in man was studied in detail by Yo agent are related20). In this connection, the concentration shida et al29). Almost all the excreted amount is excreted of the contrast agent in the bile capillaries increases to a in the urine within 24 hours, that is, 14.5±2.6% and fixed level according to the contrast agent's blood concen- 15.7±3.3% 24 and 72 hours, respectively, after a single tration. But the bile capillary concentration does not rise intravenous injection of Biligrafin, that is IVC, and 15.6± above the fixed level, though the blood concentration may 2.0% and 16.2±2.0% 24 and 72 hours, respectively, after increase. The rate of excretion into the bile at the maxi- drip infusion administration, that is, DIC. In the stools, mum concentration in the bile capillary is called the 15.3±9.6% and 62.3±14.2% is excreted by 24 and 72 transport maximum (Tm). hours, respectively, after IVC and 15.3±9.6% and When a contrast agent is excreted into the bile, the bile 65.0±3.8% by 24 and 72 hours, respectively, after DIC. flow volume is increased by osmotic cholagogic activity21). In the gallbladder, bilirubin is concentrated about 20- Characteristics of indirect cholangiographies fold, and cholesterol and bile acid is concentrated by about 5-10 times. The bile itself is concentrated by about Oral cholecystography 10 times. Water in the contrast agent stored in the gall- As stated previously, oral cholangiography requires the bladder is also absorbed. Imaging of the gallbladder absorption of a contrast agent in the intestinal tract as the requires a 0.25-1.0% the concentration of iodine in the first step. Image quality is also influenced by poor absorp- gallbladder22). When glucuronidase-producing bacteria tion of the contrast agent due to nausea, retching, vomit- are present in the gallbladder, the conjugation with ing and accumulation of the agent in the stomach foll- glucuronic acid weakens and the contrast agent occasion- owed by a deformed upper digestive tract, and to diar- ally precipitates on the wall of the gallbladder23). rhea. It is difficult for Telepaque to be dissolved after a The contrast agent is excreted into the duodenum long contact with gastric acid, and the absorption is through the gallbladder and the common bile duct. disturbed by a decrease in pH in the intestine due to According to Schroder et al.24), 65% of the administered hyperchlorhydria and pancreatic exocrine dysfunction, 72 Annals of Cancer Research and Therapy Vol.7 No.2 1998 resulting in an unsatisfactory cholangiograph. Optimal and its combined use with OC36). However, a report gallbladder opacification can be obtained 14-19 hours, 17 showed that the simultaneous administration of Biligrafin hours on the average, after the administration of the oral and Telepaque disturbed the excretion of Biligrafin37). contrast agent30). Cholecystography taken 12 hours after the administration should be evaluated again.