Review Article

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. Reading of Rectal cholecystography the cholecystography is sometimes disturbed by gas and Biloptin, which is quickly absorbed by the intestine, is retention of the contrast agent in the intestinal tract. used in RC. A mixture of 3-6g of Biloptin with 20-30ml Four-day administration of Telepaque31), double dose of lukewarm water or 20% glucose solution is administer- and divided administration of Biloptin, and simultaneous ed rectally. The most effective imaging of the gallbladder administration of sodium bicarbonate (5g) and Tele- can be obtained six hours after administration38). RC is paque19) are modifications of oral cholangiography. applicable to infant patients, patients with severe vomit- Biloptin is easily absorbed in the intestine and makes the ing, the inability to absorb the agent, or paralytic ileus. visualization of gallbladder possible within 3-4 hours after administration. The four-day administration method Gallbladder emptying with Telepaque is called biliary calculography. Biliverdin The following are obtained by gallbladder emptying in converted from bilirubin reacting with the iodine in the cholangiography: (1) better visualization of the bile Telepaque on the surface of the gallstones becomes imper- ducts, (2) separation of the gallbladder from the intestinal meable to X-rays, showing a rim sign, and induces a gases, (3) detection of a lesion which cannot be diagnosed positive sign of the bilirubin stones. This method is before contraction, and (4) functional approach to the effective for detecting stones in the bile duct, many of biliary tract. The normal gallbladder generally contracts which are bilirubin stones, as well as stones in the gall- by more than one half, 45 minutes after administration of bladder. two egg yolks or 13g of Daiyan granules as a contstricting function test. However, some reports maintain that the test Intravenous cholangiography is of no clinical significance39). After Biligrafin was developed in 1956, IVC became popular. DIC is thought to have been carried out first by Diagnostic ability and limitations of indirect Valera-Fuentes et al. in 1957, administering intravenous cholangiographies drip of the mixture of hypertonic glucose solution, Bili- grafin, insulin, and morphine. The biliary tract system can Since contrast agents are excreted from the liver prior to be imaged within a relatively short time without the indirect cholangiography, whether or not image is satis- process of absorption in the intestinal tract with IVC. The factory naturally depends on the hepatic function in the slow infusion of the contrast agent in DIC increases the case of indirect cholangiography. binding of the agent to serum albumin and thus the In cases of liver dysfunction such as hepatitis and liver imaging capability of cholangiography. By IVC the gall- cirrhosis, the gallbladder could be imaged in 67% and 50% bladder is imaged more faintly than by the oral method, of the cases when serum bilirubin levels were less than but the common bile duct is imaged by IVC more distinct- 1.0mg/dl and less than 2.0mg/dl, respectively. When ly than by the oral method. According to a study by serum bilirubin was more than 3.0mg/dl, the gallbladder Matsumoto et al.32), IVC or DIC was successful in more could barely be imaged. When Bromsulphalein(R) (BSP) than 40% of the patients whose gallbladders could not be test at 45 minutes (R45 BSP) or indocyanine green (ICG) imaged by OC, and imaging of the common bile duct was loading test at 15 minutes (R15 ICG) showed more than possible in 46% by IVC and in 71% by DIC. However, 30%, it was not imaged40). IVC and DIC could still not manage to image the gall- According to Matsumoto34), a limitation of IVC is bladder or the bile duct in half and one-fourth of the observed when R45 BSP, total bilirubin, Al-P, GOT, and patients respectively. GPT are less than 25%, less than 4mg/dl, less than 20 Some methods are modified from IVC in order to KAU, 80, and lees than 60, respectively. increase the ability to image the gallbladder and to The limitation of DIC was investigated in detail by shorten the time. They are intravenous injection of sor- Namihisa et al.40). The rate of imaging by the usual DIC bitol prior to intravenous injection of the contrast (DIC-A) is 70% when the serum bilirubin level is less agent33), the combined use of morphine, pentazocine and than 3mg/dl, but it decreases to only 36% when the level an anticholinergic for the purpose of contracting the Oddi is more than 3.0mg/dl. Imaging by DIC (DIC-C) by its sphincter and increasing the ability to image the bile duct, administration at a low concentration over a long period the use of adrenocorticosteroid to suppress inflammation is possible when serum bilirubin is 5.0mg/dl or less. The of the biliary ststem34), the application of tomography35), imaging of the gallbladder is limited when Al-P is 20

Significance of cholangiography for ESWL and gallstone dissolution therapy 73 KAU, LAP 3000(Goldberg's modification) , γ-GTP 300 result, gallstones were demonstrated in six patients (33%). U (Orlowski's modification) . KICG 0.50, HCG 0.0200, When DIC was undertaken in 38 patients with OC show- and R15ICG 30%. The imaging of the bile duct is limited ing negative result, gallstones and incarcerated calculi when AI-P is 2OKAU, LAP 500U , γ-GTP 300U, GOT were detected in 33 (87%). Common biliary calculi which 200U, GPT 200U, KICG 0.100, aICG 0.1000, and R15 were not revealed by OC were imaged by IVC and DIC ICG 20%, In regard to intrabiliary pressure , it is believed in five of six (83%) and in 11 of 17 (65%), respectively. that indirect cholangiography is impossible when the Calculi were detected in the gallbladder and the common pressure exceeds 35cm H2O. Maeda et al.41) performed bile duct by IVC and DIC in three of five (60%) and 22 DIC on 30 patients in whom the results of oral cholangio- of 25 (88%), respectively. Furthermore, two of five (40%) graphy were negative, and reported that the gallbladder calculi in the gallbladder which could not be demonstrat- and the bile duct were imaged in 40% and 77%, respective- ed by DIC, five of six (83%) choledocholiths, and two of ly. McNulty et al.42) compared IVC with DIC in 21 three (67%) calculi in the gallbladder and the common patients with jaundice, and reported that the gallbladder bile duct were definitely diagnosed by ERCP. could be imaged by IVC and DIC in 10% and 52%, The authors1) examined 24 patients with liver and respectively, and that the bile duct could be imaged by biliary tract diseases in whom ERCP, CT, and US were IVC and DIC in 76% and 92%, respectively. undertaken during the same period. Of these patients, On the other hand, imaging rates by cholecystography correct diagnosis was obtained in 14 (58%) by ERCP, in were determined in patients with Dubin-Johnson syn- 11 (46%) by CT, and in 13 (54%) by US. The rate of drome, that is constitutional jaundice, and Rotor hyper- correct diagnosis of cholelithiasis based on ERCP was bilirubinemia. The rates obtained by OC and IVC were high; of nine patients with cholelithiasis, correct diagno- 27.5% and 30.5%, respectively in patients with Dubin- sis was made in seven (78%) by FRCP, two (22%) by CT, Johnson syndrome, and were respectively 75.9% and 43.7 and six (67%) by US. The rate of correct diagnosis by CT % in patients with Rotor hyperbilirubinemia. In other was very low. Of four patients with choledocholith, cor- words, there is no difference in the positive rate between rect diagnosis was obtained in three (75%) by ERCP, two the oral and the intravenous method in the former (50%) by CT, and two (50%) by US. ERCP makes it patients, but the number of patients with positive results possible to determine pathophysiological changes or to increases when the duration of cholecystography is pro- grasp minute abnormalities such as abnormalities in the longed. On the other hand, in the latter patients, the rate confluence of the hepatopancreatic ducts in cystoma of the of imaging seems to be increased by infusing a contrast common bile duct and the fine features of the mucosa in agent at a low blood concentration for a long time, adenomyomatosis of the gallbladder which are not suggesting that the oral method is effective 43).Goodman et revealed by OC, IVC, or DIC. al.44) studied the effect of IVC in 128 patients with common bile duct diseases in which a definite diagnosis was Side effects and complications of indirect cholangiographies made based on ERCP, cholangiography during surgery, choledochotomy, and biopsy. The imaging of the com- The incidence of side effects in OC is definitely lower mon bile duct was satisfactory in 70 (55%), slightly satis- than that in IVC. Their severity is also less. However, it factory in 30 (23%), and poor in 28 (22%). Correct has also been reported that the incidence of the side effects diagnosis could be made by IVC in only 23 (55%) of the of OC is increased by sensitization after periodic repeated 42 in whom definite diagnosis was obtained, posing a examinations. The following are enumerated as the side question about the significance of IVC in the diagnosis of effects: respiratory system symptoms (tachypnea, common bile duct disease. Darnborough et al.45) also dyspnea, asthmatic attack, pulmonary edema, laryngeal obtained a 50% rate of correct diagnosis of common bile edema), cardiovascular system symptoms (bradycardia, duct disease by IVC. decreased blood pressure, cyanosis, shock, thoracic Sargent et al.38) reported on rectal cholecystography. zonesthesia), nephrotic symptoms (anuria), systemic itchy They administered Biloptin and Solu-Biloptin rectally to sensation, etc. Contraindications to the use of indirect 43 patients with bile duct disease and compared these cholangiography are macroglobulinemia, iodine hyper- contrast agents. There was no difference in the imaging sensitivity, and hyperthyroidism. Cholecystographic con- between them; that is, the gallbladder could be well trast agents occasionally cause albumin in the urine to imaged in 58% (87%, if the cases in which the imaging was become positive and they have also been shown to induce faint are included). acute renal disturbance in animal experiments. Scholz et Tsuneoka et al.46)demonstrated gallstones in 61 of 122 al.47) reported that the incidence of side effects of IVC is patients (50%) with cholelithiasis by OC. When IVC was 10% and that it is decreased to 4.3% by pretreatment with undertaken in 18 patients with OC showing negative an antihistaminie. They also concluded that the incidence

74 Annals of Cancer Research and Therapy Vol. 7 No. 2 1998 of relatively severe side effects such as nausea, vomiting, and dissolution therapy for gallstones have become hypotension, and dyspnea is about 1%. Goodman et al.44) evaluated as clinically useful, the value of indirect cholan- also reported an incidence of 1.4% (2 of 140). According giography consisting of OC, IVC and DIC should be to Frommhold48), 22 of about 6,200,000 patients (about reconsidered. 0.00035%) showed potentially fatal symptoms after IVC, and 17 of the 22 (about 0.00027% of the total) died. References Pereiras et al.49)reported the incidence of complications 1) Morishita T, Yokoyama Y, Eimoto A, Shiozaki H, Iwahashi of ERCP and PTC as 2.2% and 3.0%, respectively. In an H, Terada S, Ishii H. Combination of ERCP, CT and US in the diagnosis of liver, biliary tract and pancreatic diseases. investigation by the American Endoscopic Association in Ann Cancer Res Ther, 5: 113-119, 1997. 197450),they reported 93 complications as a result of 2) Simeone JF, Ferrucci JT Jr. New trends in gallbladder imag- ERCP performed 3,884 times, a morbidity rate of 21.6/ ing. JAMA, 246: 380-383, 1981. 3) Hoogerwert WA, Soloway RD. Epidemiology, pathogenesis, 1,000 (2.2%) and a mortality rate of about 0.13% (5 cases). and treatment of gallstones. Current Opinion in Gastroenter- There have been no deaths among the 1,199 patients in ology, 14: 413-416, 1998. whom ERCP was undertaken at Shizuoka Red Cross 4) Abel JJ, Rowntree LG. On the pharmacological action of some Hospital for the past 11 years. When the serum amylase phthaleins and their derivates, with special reference to their action as purgatives. J Pharmacol Exp Therap, 1: 231-237, level was determined in the period following ERCP, the 1909. level increased greatly or moderately in 12 of 29 patients 5) Graham EA, Cole WH, Copher GH. Visualizations of gall- (41.4%) two days after ERCP and in eight of 39 (20.5%) bladder by the sodium salt of tetrabromophthalein. JAMA, 82: 1777-1778, 1924. three days after ERCP51) 6) Morishita T, Shiozaki H, Inahuku T. [Indication for cholan- In summary, OC has the following advantages: (1) It giography in hepatobiliary-biliary diseases]. J Shizuoka Red is easy to administer and is appropriate for screening and Cross Hosp, 8: 6-13, 1988. (Japanese) 7) Bruckhardt H, Muller W. Versuche uber die Punktion der physical mass examination. (2) Few side effects are in- Gallenblase and ihre Roentgendarstellung. Dtsch Z Chir, 162: duced. (3) It is inexpensive. OC has the following dis- 168-172, 1921. advantages: (1) The imaging of the bile duct is poor. 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