Ali holecistektomija vpliva na oddijev sfinkter in ampulo papile vateri? Does cholecystectomy affect the sphincter of oddi and the ampulla of vater? Avtor / Author Marjan Skalicky12 Ustanova / Institute 1Univerzitetni klinični center Maribor, Klinika za interno medicino Maribor, Slovenija, 2Univerza v Mariboru, Medicinska fakulteta, Maribor, Slovenija, 1 University Medical Centre, Division of Internal Medicine, Maribor, Slovenia, 2University of Maribor, Faculty of Medicine, Maribor, Slovenia Ključne besede: papila Vateri, sfinkter Oddi, holecistektomija, endoskopski ultrazvok Key words: papilla of Vater, sphincter of Oddi, cholecystectomy, endoscopic ultrasound Članek prispel / Received 10.01.2011 Članek sprejet / Accepted 25.03.2011 Naslov za dopisovanje / Correspondence Prim. doc. dr. Marjan Skalicky, dr. med. Klinika za interno medicino, Univerzitetni klinični center Maribor, Ljubljanska ulica 5, Sl-2000 Maribor, Slovenija Telefon +386 23212852 E-pošta: koimed@ukc-mb.si Izvleček Namen: Ker ima 20-50 % holeci-stektomirancev tudi po operaciji žolč-nih kamnov nadaljnje dispeptične težave, želim dokazati, da del teh težav ne izvira iz primarne bolezni žolčnika s kamni, ampak so drugega, natančneje duodenalnega izvora. Metode Z endoskopskim ultrazvokom (EUZ) sem pred operacijo (AOP) žolčnih kamnov pregledal 80 bolnikov. Tri mesece po operaciji (POP3) in 6 mesecev po njej (POP6) sem preiskavo ponovil. 50 operirancev je bilo simptomatskih, 30 pooperativno asimptomatskih. Pri vseh sem opravil analizo papile Vateri (PV) s posebnim poudarkom na analizi vidljivosti sfinkterja Oddi kompleksa (SOK) in ampule papile (AP). Rezultati: Vidljivost SOK je signi-fikantna v meritvah AOP/POP3 (p < 0.05) iz prikazanih sprememb. Prav tako je signifikantna primerjava Abstract Purpose: About 20-50% of chole-cystectomized patients complain of dyspeptic problems after gallstone surgery. I hypothesized that some of these problems do not arise from primary gallbladder disease, but are due to prob-lems of duodenal origin. Methods: I examined 80 patients using endoscopic ultrasound (EUS) before gallstone surgery (AOP). I repeated the examination 3 months (POP3) and 6 months (POP6) after the surgery. Fifty patients who underwent surgery were symptomatic; 30 were asymptomatic. In all patients, an analysis of the papilla of Vater (PV) was carried out with a special focus on the visibility of the sphincter of Oddi complex (SOC) and the ampulla of papilla (AP). Results The visibility of the SOC was significant in the measurements AOP/POP3 (p<0.05). The comparison POP3/POP6 (p<0.001) was also POP3/POP6 (p < 0.001). Vzorec obnašanja AP (AOP/ POP3, POP3/POP6, AOP/POP6) v različnih meritvah ni signifikanten (p > 0.05). Linearno zvečanje odstotka nevidnih AP (76 %, 78 %, 80 %) kaže na druge mehanizme sprememb, kot sem jih ugotovil pri vidljivosti SOK 52 % (AOP), 72 % (POP3) in 50 % (POP6). Zaključek Holecistektomija očitno deluje incidentalno na vidljivost SOK. To potrjujejo klinične izkušnje v potrebnem rekonvalenscentnem dietetnem režimu nekaj mesecev po operaciji, ki so potrebne za »reprogramiranje SOK-a«. AP, ki se obnaša po svoji embrionalni in histološki zasnovi po duodenalnem vzorcu (SOK po biliarnem), pa kaže počasne nesignifikantne linearne trende zvišane nevidljivosti. significant. The behavior pattern of the AP (AOP/POP3, POP3/POP6, AOP/POP6) in various measurements was not significant (p>0.05). The linear percentage increase of non-visible AP (76%, 78%, and 80%) indicated different changes in the mechanism with respect to visibility of the SOC; 52% (AOP), 72% (POP3) and 50% (POP6). Conclusions: These data showed that cholecystectomy affected the visibility of the SOC. The AP, with its embryologi-cal and histological disposition based on a duodenal pattern (SOC is based on a biliary pattern), showed non-significant linear trends of increased non-visibility. INTRODUCTION Langenbuch (1) in 1882 reported that patients who underwent cholecystectomy as therapy for gallstone disease experienced unpleasant effects. Pribram (2) in 1950 described such effects as "postcholecystectomy syndrome" (PHS). He suggested three possible reasons: immediate consequence of the surgery; biliary symptoms despite surgery; or misinterpret nonbiliary symptoms. The main focus of our research is anomalies of the latter. The prevalence of PHS is 20-50% (3). For disorders that appear with a non-biliary etiology, we can assume that they are partially dependent upon dysfunction of the upper alimentary canal and not with gallbladder removal. Studies in which the gallbladder remained in situ after extracorporeal shockwave lithotripsy (ESWL) showed that the reason for PHS was probably not due to the biliary system. About 20-40% of these patients also report problems related to PHS (4). Rädecke found a significant correlation (p<0.005) between preoperative symptoms and outcome (5). To analyze and comprehend the non-biliary etiology of PHS, it is necessary to understand the specific anatomy of the distal bile duct, sphincter of Oddi, the ampulla of Vater, and the papilla of Vater. The choledochus forms by the junction of the hepatic duct and cystic duct, and is joined by the duct of Wirsung in the pancreatic part. At the point of entry of the duodenal wall, the ampulla of the papilla (AP) is formed, which is a component part of the papilla of Vater (PV). To understand the functioning of the sphincter of Oddi complex (SOC), it is necessary to understand the anatomy of the distal choledochus. The lower choledochal sphincter muscle is formed in the intramural part. The musculature is progressively weakened when ascending. The muscular meshwork of the upper choledochal sphincter is formed in the distal part of the intrapancreatic choledochus. The duct of Wirsung is also surrounded by muscular layers in the immediate vicinity of the junction, where both musculatures are linked and continue their way towards the AP. This miniature muscle fills the bile duct and the gallbladder in a retrograde fashion; it regulates the flow of bile and secretion of pancreatic fluid (6). An analysis of patients who underwent cholecystectomy demonstrated that the sphincter activates itself irrespective of the intestinal-duodenal musculature (7). It is very important that development of the musculus proprius choledochi in an embryo is 5 weeks after that of the intestinal duodenal musculature (8). The functionality of this valve mechanism on the level of the junction is directly associated with erection of the papilla and the emptying of bile and pancreatic fluid. The SOC is influenced by numerous gastrointestinal hormones and neuroendocrine agents that affect the basal pressure and phase contractions. Abnormal functioning of the SOC causes colic-like pain (9). It is not known if the function of the SOC and the pancreatic duct are independent of each other (10). The sphincter choledochus and the sphincter of Wirsung together form the first portion of the AP. Muscles and their fibres reach into the submucosa, where they entwine with glands and surrounding tissue. They then form the SOC (11). The SOC has a high pressure and is 6 mm from the orifice of the papilla. It covers 10-15 mm of the distal choledo-chus, and comprises choledochal, pancreatic and ampullary parts. The coordination of these three segments is not known (12). The contractile activity of the SOC is measured using manometry. Pressure in the duodenal wall (pars intramuralis), SOC and the choledochus are recorded. The measurements indicate various pressures and different activity phases (13). Functional manometry confirms the separate activity of the SOC lying in the ampullo-choledochal segment of the PV of the AP, which is the duodenal functional model of embryo development (8, 14). The AP is formed and continues towards the orifice of papilla. Muscular fibers are very rare, and "embrace" glandular structures. The primary structure is the duodenal mucosa. Its epithelium forms the ampullary wall. Brunner's glands and some connective tissue are in the submucosa. The muscularis propria is part of the intestinal musculature. The blood flow of the PV is very specific. Arterial blood flow is low because the median vein diameter of the plexus arteriosus is 0.98 mm (15). As a consequence, all tissue characteristics and physical changes of the SOC and AP have diverse ultrasound (US) echogenicity, impedance, reflectance, diffusion, and this is termed "scattering". Unlike percutaneous US, the accessibility of the subtle organogram of the anatomical structures of the PV with the EUS is considerably more precise and reliable. In health, the size of the PV is between 20-25 mm2. It has the form of a conventional triangle with a height of 0.6 mm. This form is taken into consideration when calculating the surface area (11). Enlargement of the PV by 2-4-fold has been reported for patients with gallstones (11). The SOC and AP have different embryonic, anatomic and histological genesis. Hence, one would expect different behaviours of the SOC and AP in gallstone disease, during surgery, and the postoperative period. I analyzed the behaviours mentioned above using endoscopic ultrasound (EUS) as a semi-invasive method. This represents normal stress for the patient, just like classical endoscopy (12). MATERIALS AND METHODS The study protocol was approved by the Ethics Committee of the Faculty of Medicine, University of Maribor, (Maribor, Slovenia). All patients provided written informed consent to be included in the study. The study involved 80 cholecystectomized patients with no evidence of choledocholithiasis or cholesta-sis. Fifty of these patients experienced early atypical complaints such as bloating, distension, nausea, and pain in the upper abdomen. The remaining 30 patients had no symptoms in the same period after cho-lecystectomy. EUS, as well as visibility of the SOC and AP lumen was evaluated in all patients. The results were compared with normal values, and parameters of the PV. Echogenicity (scattering) is dependent upon the impedance between various tissues as well as the velocity and energy of reflected US waves. The greater the reflection of sound waves (scattering) the brighter ("hy-perechogenic") the structure will appear. Conversely, the smaller the reflection of sound waves, the less bright ("hypoechogenic") the structure will appear. A mid-point between these extremes is a structure that appears to be iso-echogenic. Echogenicity is not dependent upon tissue thickness (13, 14). Histologically, the SOC and AP comprise epithelium and mucosa. The submucosa consists of various glands, vascular structures, tissue, muscles, and interstitial fluid (15, 16). I analyzed the sonograms of the PV of 24 healthy subjects who underwent a full medical examination in Maribor (Slovenia) and Zagreb (Croatia). These analyses did not show the PV structures of the SOC and AP. This indicated that the normal PV was EUS isosonic in its isoechogenic substrate (17). Also, the size (20-25 mm2), height HPV (6 mm), and width (12 mm) of the PV were noted (11). In addition, no sex-related differences were observed. A GF UM 20 (Olympus Optical, Shibuyaku, Japan) machine was used with a 7.5-MHz ultrasound probe at 360° rotation. When observing the PV, the probe was placed in a perpendicular and axial position in the descending duodenum. I categorized the visibility of the SOC as "well visible", "less visible" or "not visible" in the sonogram of the PV. The height of the papilla (HPV) was measured separately (Figure 1). Description of the appearance of the AP was based on whether the lumen of the ampulla was visible or not (Figure 2). Statistical analyses was based on the values measured in cholecystectomized patients before cholecystecto-my (AOP), 3 months after gallbladder removal (POP 3) and 6 months after gallbladder removal (POP 6). The Mann-Whitney-Wilcoxon non-parametric test and the Stuart x2 test were used. The results were compared with normal values measured in 24 healthy subjects. TEACH [NG HOSPTTSL MflPIIEOR GASTROENT. DEPflR IMEN T IS; fl. n. 1943 FßS:?.5KHz RKG : 4c rn Ö -RNG: 4c i"- <«»- HttSTBNCE :DO.sen 5UREME11T. 1 , a 1 ■ - . i ÜIR-h Figure 1. SOK - Sphincter of Oddi Complex less visible. PV - Papilla of Vateri, CBD Common Bile Duct, +..+ Height of the PV (0.8 cm), x...x Width of the PV (1.5 cm) TEACHING HOSPITAL MSRIBOR GflSTRuENT.DEPHRTMENT 0 HOLE - MEASUREMENT , 1 w pu 15-10-02 10: IS: 56 ID: R. M. 1950 FRS:?. SMHz ■RNG: 6cri Gfll N - 81 C0NT:3 -flee: 1 -DISTANCE - 00 7cra :: 01. Ocn j«-: :_L5_ Figure 2. SOK - Sphincter of Oddi Complex is well visible. PV Papilla of Vateri, CBD Common Bile Duct, +...+ Diameter of CBD (0.7 cm), x...x Height of the PV (1.0 cm), PAP lumen of Ampulla of PV RESULTS The group of 50 patients consisted of 19 men and 31 women. The mean age for men and women were 58 years and 63 years, respectively. The youngest patient was aged 19 years and the oldest 83 years. In the group of 30 asymptomatic patients, 16 were men and 14 women. The mean age for men was 53 years and for women was 61 years. The control group consisted of 11 men and 13 women. The youngest was aged 24 years and the oldest 79 years. The median age was 52 years for men and 57 for women. All our patients were from the region of Maribor (Slovenia) and Zagreb (Croatia). The differences between men and women in HPV and visibility of the AP lumen were not statistically significant, so the results were analyzed for the sam- ple as a whole. Table 1 shows the calculated HPV in three time periods in 50 symptomatic patients. Table 2 shows the percentage differences in echogenicity of the SOC measured thrice at different time periods. The data in Tables 1 and 2 are for all 50 symptomatic patients. Table 3 and Figures 1 and 2 show the appearance of the SOC of the PV during measurements before surgery as well as 3 and 6 months after surgery. Table 4 shows HPV measurements before cho-lecystectomy as well as 3 months and 6 months after cholecystectomy in 30 asymptomatic patients. Table 5 shows results of measurements of the SOC of the PV before cholecystectomy as well as 3 months and 6 months after cholecystectomy in 30 asymptomatic patients. The analysis confirmed the non-visibility of the SOC before surgery and 6 months after surgery, whereas visibility was best 3 months after surgery. The Table 1. HPV measurement in 50 symptomatic patients X SD Median Min Max X2 p AOP 9.9 ± 3.4 9.0 6.0 21.0 POP3 10.8 ± 3.6 10.0 6.0 24.0 10.92 < 0.005 POP6 9.4 ± 2.3 8.5 6.0 16.0 AOP:POP3 3.05 p < 0.05; AOP:POP6 1.26 p > 0.05; POP3:POP6 3.67 p < 0.001 AOP: prior to surgery; POP3: 3 months after surgery; POP6: 6 months after surgery. Table 2. Measurements of the SOC of the papilla of Vater before cholecystectomy as well as 3 months and 6 months after cho-lecystectomy in 50 symptomatic patients 1. Measurement 2. Measurement 3. Measurement Visibility AOP POP3 POP6 n % n % n % Well visible 5 10.0 8 16.0 - - Less visible 21 42.0 28 56.0 25 50.0 Not visible 24 48.0 14 28.0 25 50.0 AOP: prior to surgery; POP3: 3 months after surgery; POP6: 6 months after surgery, SOC of the PV after cholecystectomy in 50 symptomatic patients Table 3. Appearance of the SOC of the PV according to measurements AOP Well Less Not visible visible visible Well visible 5 2 1 POP3 Less visible 0 14 14 Not visible 0 5 9 (Stuart) X2 ii . df = 2 p < 0.05 AOP Well Less Not visible visible visible Well visible 0 0 0 POP6 Less visible 5 9 11 Not visible 0 12 13 (Stuart) X2 = 5.04 df = 2 p > 0.05 POP3 Well Less Not visible visible visible Well visible 0 0 0 POP6 Less visible 8 13 4 Not visible 0 15 10 (Stuart) X2 = 14.37 df = 2 p < 0.001 AOP: prior to surgery; POP3: 3 months after surgery, POP6: 6 months after surgery. df - Degree of Freedom visibility was significantly low (p<0.001) 6 months after surgery. Table 6 describes the appearance of the ampulla lumen. It showed a tendency of progressive non-vis- ibility of the linear type in 30 asymptomatic patients. The visibility of the lumen of AP was inversely proportional to the visibility of the SOC. Table 7 shows the visibility of the AP lumen according to measurements in 50 symptomatic patients. Changes in the visibility of the AP lumen were not significant in any measurement (p>0.05). Table 8 shows the results of the analysis of the HPV as well as the visibility of the SOC and AP lumen. The statistical significance of the HPV and the visibility of the SOC were equal. This confirmed the identity of the anatomical location of the SOC with respect to the HPV: AOP/POP3 (p<0.05), POP3/ POP6 (p<0.001). The measurements between AOP and POP6 (p>0.05) were not significant. The HPV in symptomatic and asymptomatic patients was higher than in the normal population (7-9 mm). The results of the visibility of the AP lumen were not significant (AOP, POP3, POP6, p>0.05). There were only minor linear non-visibility trends for the AP (76%, 78%, and 80% at AOP, POP3 and POP6, respectively). The visibility trends of the SOC deviated considerably (52%, 72%, and 50%, respectively) for the three measurements. The visibility of the SOC was significant in the measurements AOP/POP3 (p<0.05) and POP3/POP6 (p<0.001), but not for AOP/POP6 (p>0.05). Identical changes were also observed in asymptomatic patients, so an unknown agent did not cause the complaints in patients. DISCUSSION Despite its small size (PV is 20-25 mm2 in normal subjects), the PV in cholecystectomized patients (7590 mm2) is very important (18). Furthermore, it is very important to be familiar with structures such as the SOC and AP. For correct interpretation and analyses of EUS findings, a good knowledge of mi-croanatomy is required. In his supplemented edition of embryonic histomorphology, Acosta (19) identified the ampullary choledochal segment of the PV as a functional smooth muscle entity of SOC PV. Table 4. HPV measurements before cholecystectomy as well as 3 months and 6 months after cholecystectomy in 30 asymptomatic patients X SD Median Min Max X2 p AOP 9.8 ± : 3.2 9.0 5.9 21.0 POP3 10.9 ± 3.7 10.0 6.0 23.9 10.73 < 0.005 POP6 9.3 ± 2.2 8.3 6.0 15.9 AOP:POP3 3.05 p < 0.05; AOP:POP6 1.26 p > 0.05; POP3:POP6 3.67 p < 0.001 AOP: prior to surgery; POP3: 3 months after surgery; POP6: 6 months after surgery. Table 5. Measurements of the SOC of the papilla of Vater before cholecystectomy as well as 3 months and 6 months after cho-lecystectomy in 30 asymptomatic patients 1. Measurement 2. Measurement 3. Measurement AOP POP3 POP6 n % n % n % Well visible 3 10.0 5 17.0 1 3 Less visible 13 42.0 16 53.0 14 47.0 Not visible 14 48.0 9 30.0 15 50.0 AOP: prior to surgery; POP3: 3 months after surgery; POP6: 6 months after surgery, SOC of the PV after cholecystectomy in 30 asymptomatic patients. Table 6. Measurements of the visibility of the AP lumen of the papilla of Vater before cholecystectomy as well as 3 months and 6 months after cholecystectomy in 50 symptomatic patients 1. Measurement 2. Measurement 3. Measurement AOP POP3 POP6 n % n % n % Lumen 7 14.0 5 10.0 1 2 Small lumen 5 10.0 6 12.0 9 18.0 Not visible 38 76.0 39 78.0 40 80.0 AOP: prior to surgery; POP3: 3 months after surgery; POP6: 6 months after surgery, SOC of the PV after cholecystectomy in 30 asymptomatic patients. Table 7. Visibility of the AP lumen according to measurements AOP Well Less Not visible visible visible Well visible 4 0 1 POP3 Less visible 3 1 2 Not visible 0 4 35 (Stuart) X2 = 1.40 df = 3 p > 0.05 AOP Well Less Not visible visible visible Well visible 0 0 1 POP6 Less visible 3 2 4 Not visible 3 4 33 (Stuart) X2 = 4.65 df = 3 p > 0.05 AOP Well Less Not visible visible visible Well visible 0 0 0 POP6 Less visible 3 5 2 Not visible 3 1 36 (Stuart) X2 = 6.32 df = 3 p > 0.05 AOP: prior to surgery; POP3: 3 months after surgery, POP6: 6 months after surgery. Moreover, he assigned the ampullo-papillary segment of the AP lumen as having an embryo-duodenal origin. Histologically, the main structures of the SOC are interlaced with the muscularis mucosa of the choledochus, the duct of Wirsung, and part of the ampullary musculature. Most of the histomor- phological structures of the ampullo-duodenal segment of the AP belong to submucosal tissue of the duodenal type. This also explains the specific behavior of the PV (8). Considering the non-visibility of the AP lumen (a normal lumen was not visible), we concluded that there were linear trends of improvements in this part of the papilla (76%, 78%, and 80%). However, the behavior of the proximal choledochal part of the SOC did not show this type of linearity. An explanation for this observation could be due to the arterioles of the submucosal plexus lying towards the orifice of the PV. This vein system is harmonized within its own functional blood flows followed by various vasoactive substances (e.g. hormones) and neural innervation. It is about the flow through the capillary vessel network of the duodenal type. Brunner's mucosal ampullo-pap-illary glands are activated by the same mechanisms. This could be due to an adenomatous type of stimulation of the AP with major secretion of mucus and non-peptic duodenal papillitis (20). It is probably a form of functional papillitis with characteristics as in functional duodenopathy of non-peptic origin (21). Data on the chronic problems of dyspeptics (22, 23, 24) after a cholecystectomy are in accordance with 20% of visible AP found in the present study. The SOC consists of three muscles forming the proximal portion of the ampulla. The entire complex is 10-15-mm long. Manometric analyses show synchronous motor activity of the upper alimentary canal (25). The most surprising feature of the activity analysis of the SOC are the pressure waves with a frequency of 4-5 impulses in 4 min with the duration of 4-5-s each. An amplitude height <130 mmHg is of great importance, and often exceeds values of systolic blood pressure (yet always exceeds the values of diastolic blood pressure). The strongest phase contractions are manifested 6-8 mm in the distal choledochus. This is also the site of the ampullary choledochal segment of the HPV, where the SOC is positioned. Wave phase sequences are significantly elevated in the form of repeating waves. They are more frequent in cholecystectomized patients, who Table 8. Correlation between HPV and the visibility of the SOC and AP lumen HPV Visibility of the SOC Visibility of the AP lumen AOP/POP3 p<0.005 p<0.05 p>0.05 AOP/POP6 p>0.05 p>0.05 p>0.05 POP3/POP6 p<0.001 p<0.001 p>0.05 AOP: prior to surgery; POP3: 3 months after surgery, POP6: 6 months after surgery. usually have a normal endoscopic retrograde cholangiopancreatography (ERCP) (26). The present study showed that the SOC and AP lumen are practically invisible in a normal papilla. EUS showed a normal papilla that was iso-echogenic. Various diseases of the biliary tract or surgeries can affect the papilla (27, 28, 29). This leads to changes in EUS echogenicity. The same is true for the visibility of the AP. 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