A New Preoperative Categorization and Potential Preoperative Indicator for Cysto-Biliary Fistula in Hydatid Hepatic Disease Open Access

We retrospectively collected data on a total of 131 patients who were surgically or only endoscopically treated for HHD at Adana Numune Training and Research Hospital after receiving institutional ethics committee approval (A.N.E.A.H.E.K. 2013/35). The computerized and documentary archives of patients were used in this study. The patients with distant hydatid cysts and preoperatively complicated cysts such as liver abscesses and spontaneous cyst rupture, as identified by clinical features, laboratory findings, ultrasonography, or/and computed tomography (CT), were excluded from the screening. All patients had available complete blood cell count (Cell-Dyn 3700, Abbott Diagnostics Division, Irving, Texas) and liver function test (Cobas Integra 800 Chemistry Analyzer, Roche Diagnostics, Indianapolis, Indiana) results. All patients received albendazole (10 mg/kg per day) before and after invasive treatment. Patients who underwent only ERCP and preoperative ERCP with cholangiohydatidotis and patients who underwent surgery with findings of bile-stained perioperative cyst content or postoperative biliary leakage received a diagnosis of CBF. Fifteen patients with obvious preoperative clinical symptoms of CBF such as obstructive jaundice (total bilirubin > 2 mg/dL, direct bilirubin > 1.5 mg/dL or other clinical and radiologic signs), acute cholangitis, or radiologic signs such as communication between the cyst wall and bile ducts and dilation of the main bile duct were defined as having symptomatic HHD (Fig. 1). All of the symptomatic patients underwent preoperative treatment or only ERCP. Thirteen of these patients (86.7%) had CBF. They were classified as having frank CBF and received an intervention of endoscopic sphincterotomy. Five of the patients receiving a CBF diagnosis did not undergo surgery after being treated by therapeutic ERCP because of their poor health status due to other medical conditions. We did not identify CBF in the 2 remaining symptomatic patients, and they underwent surgery. The remaining 116 patients comprised our study population; these patients were without obvious preoperative radiologic signs and clinical features selected from our data for determining patients in whom preoperatively diagnosing CBF is difficult. These 116 patients were categorized into 2 groups: with HLE and without HLE, named usual suspicious HHD and asymptomatic HHD, respectively. Factors associated with CBF were analyzed in 116 patients. Then, the risk for CBF was determined according to whether patients had or did not have HLE. The usual suspicious HHD group was then divided into 2 groups, group 1 and group 2, for patients with and without CBF (Fig. 2), respectively. The distribution of all patients with HHD is shown in Fig. 3. Group 1 was defined as suspected CBF. Groups 1 and 2 were compared according to the variables such as demographic characteristics, cyst features, and hepatobiliary enzyme levels. The optimal cutoff for significant continuous variables was calculated by area under the receiver operating characteristic (ROC) curve (AUC) analysis.

Information regarding the medical history associated with HHD, physical examination, radiologic, findings and laboratory findings of all patients was documented. The following data were collected: age, sex, WBC, RDW, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (T.Bil), direct bilirubin (D.Bil), ultrasonography findings such as the cyst type, diameter and Gharbi score, recurrent disease, ERCP term, surgery type, hospital stay duration, postoperative complications (systematic and local), and mortality. A standard fixed set of laboratory values was obtained on admission for all patients with HHD.

Gharbi's classification (type 1, absolute fluid collection; type 2, fluid collection with a split wall; type 3, fluid collection with septa; type 4, heterogeneous echogenic form; type 5, reflecting thick wall)¹²  was conducted according to the definition of a cyst on ultrasonography.

The upper limit of normal for liver function test results in our laboratory were as follows: AST > 32 U/L; ALT > 33 U/L; ALP > 105 U/L; GGT > 40 U/L; T.Bil level ≥ 0.8 mg/dL; and D.Bil level ≥ 0.3 mg/dL. Our data did not contain acute or chronic parenchymal or biliary liver disease and chronic hyperbilirubinemia.

All of the surgical procedures were conducted via an open approach. The surgical treatment of cysts was achieved by partial cystectomy. The protocol described below was applied for partial cystectomy in our clinic. A 3% hypertonic saline solution was used as a scolicidal agent. At the beginning of the surgery, the pericystic area was covered with 3% hypertonic saline-adsorbed compresses to protect the area around the cyst from parasitic infection. Then, the cyst was opened by making a small incision, and the cyst cavity was drained. At this time, the cyst fluid was observed to detect whether it contained bile. Hypertonic solution-soaked compresses were placed in the cavity after the germinative membrane was removed. The compresses were collected 10 minutes later to detect biliary leakage. CBF was controlled with primary suture in cases with a viable opening and with T-tube drainage in cases in which the biliary opening was not detected in the cystic cavity. Cavity management could be conducted via omentoplasty or external drainage by the individual surgeons.

Kolmogorov-Smirnov and Shapiro-Wilk tests were used to assess normality. Continuous data are presented as the mean ± SD, whereas differences between groups were analyzed by Mann-Whitney U tests. Categorical variables were analyzed with χ² or Fischer's exact tests. A P value of <0.05 was considered statistically significant. ROC analyses were used to evaluate the predictive performances of significant variables according to an optimal cutoff value for CBF. AUC values between 0.7 and 0.8 represent considerable discrimination. All statistical tests were performed using SPSS software, version 18.0 (SPSS Inc, Chicago, Illinois).

The study population included 116 patients with a mean age of 43.7 ± 16.4 (range, 19–85) years; 62 of the patients (53.4%) were women. Of the total, 21 (18.1%) patients had CBF. The rates of suspected and occult CBF were 17.2% (n = 20) and 0.8% (n = 1), respectively. Usual suspicious HHD was found in 69.8% (n = 81) of patients. Hepatobiliary enzyme levels were completely normal in 30.2% (n = 35) of patients. The type of operative procedure for cyst treatment included partial cystectomy (n = 115). Cavity management was conducted via omentoplasty (n = 110) or external drainage (n = 5). Patients who underwent surgery received a CBF diagnosis perioperatively (n = 9) by perioperative observation or postoperatively (n = 11) by biliary leakage detection. Perioperatively determined CBF was controlled with T-tube drainage (n = 9) because no invisible cysto-biliary opening was found in any of the patients. One suspected CBF patient who did not undergo surgery due to high operative risk underwent only ERCP and endoscopic sphincterotomy, with the aim to diagnose and treat this condition; this patient received a CBF diagnosis via the observation of cholangiohydatidotis. Six operated patients underwent postoperative ERCP for endoscopic sphincterotomy treatment in cases with a longer postoperative duration or with a high-output fistula. The systemic and local morbidity rates in operated patients were 10.9% (n = 13) and 20.2% (n = 24), respectively. Systemic morbidities included cardiopulmonary failure in 7.8% (n = 9) and renal failure in 2.6% (n = 3). Local morbidities included wound infection in 9.5% (n = 11), intra-abdominal abscess in 4.3% (n = 5), and biliary leakage in 9.5% (n = 11). No mortality was found in our patients within 30 days after surgical treatment or ERCP. The demographic and other clinical characteristics of the patients with and without CBF are summarized in Table 1. Age, sex, cyst diameter, cyst type, Gharbi score, recurrent disease, WBC, AST, and ALP did not significantly differ between the patients with and without CBF (P > 0.05). The RDW, ALT, GGT, T.Bil. and D.Bil levels were higher in patients with CBF than in patients without CBF (P < 0.05). The mean length of hospital stay was significant longer in patients with CBF (range, 0–50 days) than in patients without CBF (range, 2–20 days; P < 0.001). CBF was higher in patients with a higher level of any enzyme than normal for all enzymes (P = 0.004; Table 1). The risk of CBF was approximately 11-fold greater higher in patients with HLE than in patients with normal enzyme levels [odds ratio (OR), 11.1; 95% confidence interval (CI), 1.43–86.7]. The usual suspicious HHD group was then divided into 2 groups: group 1 (suspected CBF) and group 2 (no CBF but HLE). Group 1 was compared with group 2 regarding demographic and clinical characteristics, and no significant difference was found for age, sex, cyst diameter, cyst type, Gharbi score, recurrent disease, or WBC, AST, ALT, ALP, GGT, T.Bil, and D.Bil levels. Only the RDW was significantly different for CBF in the suspected CBF group. The mean length of hospital stay was also significantly longer in group 1 (range, 0–50 days) than in group 2 (range, 2–13 days; P < 0.001; Table 2). The RDW, with a cutoff value of 13.75%, presented a poor discriminating variable among patients with usual suspicious HHD for CBF (AUC, 0.661; 95% CI, 0.525–0.798). At the accepted cutoff value for RDW of 13.75%, the specificity and sensitivity were 63% and 70%, respectively.

HHD is a zoonotic disease caused by the most common form of Echinococcosis granulosus and is endemic in Turkey and in other Middle East and Mediterranean countries.^9,13  CBF is the most common complication of HHD; when not recognized or treated preoperatively, CBF can result in a series of complication in the preoperative, postoperative, or late postoperative period.^6,8  In addition, the length of hospital stay is extended by these complications of CBF, as shown in this and other studies.^5,9  Preoperative diagnosis and treatment of CBF are important for preventing these undesirable results. Preoperatively, ERCP and endoscopic sphincterotomy are suggested for diagnosis and treatment, particularly in patients with frank CBF.⁸  However, the routine use of preoperative ERCP for suspected CBF remains controversial.⁸  The most important reason for this ambiguity is patients without clinical-radiologic finding for preoperative diagnosis of CBF.^8,14  Therefore, current studies have focused on predicting occult CBF to identify patients without obvious clinical and radiologic findings who require intervention with preoperative ERCP, but these studies have resulted in some confusion regarding the preoperative choice of diagnosing frank or occult CBF. Particularly, the selection of occult CBF patients according to HLE has differed among studies, although HLE are well described as having a predictive role for CBF in patients with occult CBF.^{4,6,9,14–17}  Some studies have used occult CBF as the terminology to describe patients with HLE and without obvious clinical and radiologic findings, whereas other studies describe patients with HLE as having frank CBF.^{4–6,9,14,16}  These different descriptions of possible preoperative CBF may cause confusion for the practical use of defined predictive markers in various studies. In our initial data, the rate of frank CBF was 86.7% (n = 13) among 15 symptomatic patients. The literature mentioned that only bile duct compression could be determined in 0%–30% of patients who underwent ERCP for preoperatively probable frank CBF.⁸  Preoperative clinical or radiologic signs could be dependent on bile duct compression by cyst in our symptomatic patients without CBF. The remainder of our patients in the main data set belonged to 2 groups: patients with normal hepatobiliary enzyme levels and patients with HLE. We defined the group of patients with HLE but without any clinical and radiologic signs as usual suspicious CBF. We think that these patients may represent the source of confusion for defining occult CBF in prior studies. Moreover, patients who have only HLE as a preoperative sign for CBF have not been evaluated in the previous literature. Generally, hepatobiliary enzymes with varying levels are all affected by hepatic disease. Our data showed that CBF was more often found in patients with HLE (P = 0.004) and that the risk of CBF was higher (approximately 11-fold) in these patients. In other words, the rate of occult CBF in patients who had no preoperative signs of CBF was 0.86%, which was much lower than rates in the literature (13%–37%).^5,6  We think that our result may be connected with the clear definition of occult CBF used; these patients may not require any preoperative examination for CBF. However, CBF was identified in only 24.7% of patients with usual suspicious HHD. If these patients who have solely HLE are considered to have frank CBF, 75.3% of patients will go unnecessarily ERCP. In practice, physicians choose eligible candidates for ERCP from among patients with especially minimally raised hepatobiliary enzymes based on their individual experiences; this procedure is not standardized.

Many studies have shown that hepatobiliary enzymes were increased in patients with CBF, but there are differences in these results according to each enzyme. In their study describing a prognostic scoring system for CBF, Saylam et al found that high levels of direct bilirubin and ALP, along with a higher WBC and an elevated cyst diameter, were higher in patients with CBF; however, they excluded patients with HLE and intervened with ERCP.⁶  Demircan et al and Unalp et al found associations between CBF and HLE such as ALT, AST, ALP, GGT, and bilirubin, as well as between CBF and WBC. They included patients with any hepatobiliary enzyme levels.^5,9  Atli et al found that high levels of ALT, T.Bil, and ALP were associated with occult CBF.⁴  Our results were generally consistent with the literature. In our data on 116 patients, ALT, GGT, T.Bil, and D.Bil levels were significantly higher in patients with CBF. ALP was not a significant variable for CBF in our study. Atahan et al founded that ALP was not specific for occult CBF and that elevated GGT was the only significant variable in patients with occult CBF,¹⁴  whereas Demircan et al determined that elevated ALP levels were more specific than high GGT levels.⁹  These different results may be dependent on several reasons such as the inclusion of different patient groups in different studies, nonspecific hepatobiliary enzyme studies for HHD and CBF, especially ALP, levels not originating from the liver. Moreover, in our study, no enzyme levels showed significant differences according to whether CBF was identified in patients with usual suspicious HHD, even if the mean enzyme levels were higher in patients with CBF than in patients without CBF. A borderline relationship between CBF and the T.Bil or D.Bil was determined, but it was not significant (P = 0.56, P = 0.59, respectively). This result may be attributed to the small sample size in our study. Some previous studies have discussed that the passage of cystic fluid into minor biliary ducts and the reabsorption of bile from the cystic cavity may be responsible for the high levels of enzymes.^4,6  These comments might be not originating from the liver valid for patients with CBF, but they do not explain the high levels of enzymes in patients without CBF. Moreover, parenchymal damage and small bile duct compression, dependent on the mass effect of the cyst, may result in increased hepatobiliary enzyme levels in both patients with and without CBF.

Recent studies investigating predictive variables for CBF have generally evaluated WBC as an inflammatory marker. WBC has been defined as independent risk factor in some studies,^5,6  whereas other studies have not found any relationship between WBC and CBF, similar to our results.^4,9,14  Additionally, we found that RDW, as the only variable, was significantly higher in patients with CBF than in patients without CBF, but the AUC for RDW > 13.75 revealed unsatisfactory discrimination for CBF in the usual suspicious patients. Chronic inflammation due to occult CBF could be the source of this relationship. A positive correlation has been found between RDW and inflammatory markers such as C-reactive protein and the erythrocyte sedimentation rate in various studies.^11,18  In addition, the potential prognostic significance of elevated RDW was shown in inflammatory diseases such as acute pancreatitis, inflammatory bowel disease, and sepsis in other studies.^10,18–20  Moreover, Hu et al found a positive correlation between RDW and total bilirubin or ALP levels in various liver disease such as primary biliary cirrhosis, alcoholic cirrhosis, primary hepatocellular carcinoma, and liver cirrhosis,²¹  but they did not identify any relationship between CBF and AST or ALT levels. Elevated RDW in hepatic disease appears to be associated more with destruction of the bile epithelium than of the liver parenchyma, which may explain the elevated RDW in CBF.

Some of studies mentioned the relationship between increased cyst diameter and CBF.^4–6,9,17  The cause of this relationship can be speculated destructive effect on both the cyst wall and stretching of the bile channels due to increasing intracystic pressure with increasing cyst diameter.⁶  However, some of studies did not identify this relationship.^14,15  We also did not any find a significant association between CBF and increasing cyst diameter, although the median cyst diameter was higher in patients with CBF than in patients without CBF. Our results may be dependent on the small sample size in this study. Notwithstanding, a recently increased cyst diameter is still not an indication for preoperative ERCP in cases in which CBF is suspected.⁸ 

The limitation in our study is its retrospective nature. We could not collect data on other preoperative minor inflammation in patients, even if patients could not have a major preoperatively inflammatory condition such as an upper respiratory tract infection, which can be frequently observed. The specificity of the RDW could perhaps be increased by conducting prospective studies that consider preoperative inflammation. Additionally, our sample size may be criticized, but it is similar to that in other studies investigating CBF in patients with HHD.^2,4,6 

The risk of CBF in patients with HLE was much higher among patients who had no accompanying preoperatively clinical and radiologic signs for CBF. However, this result may not apply to frank CBF because approximately three-fourths of patients with HLE did not have CBF. Preoperatively higher RDW was defined as an independent risk factor for CBF, but the cutoff value of 13.75% was not useful for discriminating suspected CBF. Further research, with a larger sample size, is required to increase the predictive value of RDW and to identify the exact mechanisms underlying the association between RDW and CBF. We also believe that this study will guide other studies focused on patients newly defined as usual suspicious HHD and on the relationship between RDW and CBF.