Cholangiohydatidosis. Clinical features, postoperative complications and hospital mortality. A systematic review

Background Cholangiohydatidosis (CH) is an evolutionary complication of hepatic cystic echinococcosis, associated with increased morbidity and mortality. The aim of this study was to describe the available evidence regarding clinical characteristics of CH, postoperative complications and hospital mortality. Methodology/Principal findings Systematic review. Studies related to CH with no language or publication restriction were included. Sensitive searches were performed in Trip Database, SciELO, BIREME-BVS, WoS, PubMed, EMBASE and SCOPUS. MeSH and free terms were used, including articles up to April 2023. The main outcome variables were postoperative complications and hospital mortality; the secondary ones were publication year, origin and design of primary studies, main clinical manifestation, anatomical location and type of cysts, hospital stay, surgical procedure performed, reinterventions; and methodological quality of primary studies, which was assessed using MInCir-T and MInCir-P scales. Descriptive statistics, calculation of weighted averages and their comparison by least squares logistic regression were applied. 446 studies were retrieved from the searches performed, 102 of which met the inclusion and exclusion criteria. The studies analyzed represent 1241 patients. The highest proportion of articles was published in the last decade (39.2%). Reports are mainly from Turkey (28.4%), Greece (9.8%), Morocco and Spain (8.8% each). With a weighted mean of 14.3 days of hospital stance; it was verified that 26.2% of patients developed postoperative complications (74,3% Clavien y Dindo III y IV), 6.7% needed re-interventions, and 3.7% died. When comparing the variables age, postoperative complications, hospital mortality, and reinterventions in two periods of time (1982–2006 vs. 2007–2023), no statistically significant differences were found. When applying the MInCir-T and MInCir-P scales, the methodological quality of the primary studies was 9.6±1.1 and 14.5±4.3 points, respectively. Conclusion/Significance CH is associated with severe postoperative complications and significant hospital mortality, independent of the development of therapeutic support associated with the passage of time.


Introduction
Echinococcus granulosus and its various genotypes (preferably G1-G3 and G6-G7), is the etiological agent of cystic echinococcosis of the liver (CEL).This infection manifests itself three weeks after ingesting the egg and can reach 2 to 3 cm. in diameter in the liver parenchyma, three months after the infection occurred [1,2].
As CEL progresses, intracystic pressure reaches values of up to 80 cm H 2 O, producing atrophy and fibrosis of the liver parenchyma due to compression which eventually leads to biliary tree obstruction.This occurrence happens namely in those cysts located in the center of the liver.Similarly, the increase in intracystic pressure and the fragility of the cyst wall, can generate a rupture of the cyst towards the lumen of the bile ducts, developing a cysto-biliary communication (CBC); However, even if there is no cyst rupture into the bile ducts, it can manifest biochemically and radiologically as an obstructive syndrome of the bile duct, secondary to compression [3].
Consequently, the evidence suggests that the most frequent evolutionary complication of CEL, is CBC development, with a reported incidence of up to 42% [4][5][6].These communications, in relation to the diameter, can be classified as minor (or simple) and major (or frank intrabiliary rupture).Minor ones, which affect between 10% and 37% of patients with CEL, are small communications between the cyst wall and the bile ducts, where there is no passage of daughter vesicles or pieces of germinative membrane to the bile ducts.Nevertheless, in these cases fluid, protoscolex, or hydatid grit may enter the bile ducts without causing obstruction.Being asymptomatic, pre-surgical diagnosis is unlikely and minor CBCs are detected during surgery, by visualizing bile leakage or bile fistulas [6].
In contrast, major CBCs, with an incidence of 3% to 17% of patients with CEL, are characterized by broad communication between the cyst wall and biliary tree.They are frequently detected preoperatively and typically during surgery.In these cases, the contents of the cyst can spontaneously drain into the bile duct, causing total or intermittent biliary obstruction [7], expressing itself clinically as biliary colic, obstructive jaundice and cholangitis [8]; (Fig 1).Such events can progress to sepsis, liver abscess formation, acute cholecystitis and even acute pancreatitis [9][10][11][12][13][14].All of the above are situations that significantly increase the probability of developing postoperative complications [15].
Based on the pathogenic phenomena previously described, cholangiohydatidosis (CH) is defined as the presence of parasitic structures, characteristic of CEL (germ or pieces thereof, daughter vesicles or both), inside the bile duct, causing total or intermittent biliary obstruction, with or without secondary infection [8,16].
As such, it is an evolutionary complication of CEL, with a wide range of clinical manifestations that make preoperative diagnosis difficult at best.The reported prevalence is between 15.1% and 55.6%; and a cumulative incidence estimated at 0.07 cases in 5 years.It is furthermore associated with postoperative complications and in-hospital mortality of 23% and 7% respectively [15][16][17][18].
The aim of this study was to describe the available evidence regarding the clinical features of cholangiohydatidosis, postoperative complications, and hospital mortality.

Methods
This manuscript was written following the PRISMA guideline statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Study design
A systematic review was conducted following the Updated guideline PRISMA statement [19].

Eligibility criteria
Primary studies related to cholangiohydatidosis were included; without language restriction or year of publication.Editorials, letters to the editor, narrative reviews, consensus documents and discussions, and articles contaminated with patients infected with E. multilocularis, E. vogelii, or other parasites were excluded.

Information sources
The following metasearch engines, libraries, and databases were reviewed: Trip Database, SciELO, BIREME-BVS, Web of Science (WoS), PubMed, EMBASE, and SCOPUS.The search and recruitment of articles closed on April 25, 2023.

Search criteria
This was carried out using the PECO components (population study [P] 1).A manual and cross-reference search was also carried out.

Study selection
Identified documents in each information source were filtered by duplication between databases.They were subsequently examined by title and abstract, applying eligibility criteria.The articles were then extensively analyzed by 3 reviewers (CM, JR and CR), all experienced in searching and analyzing biomedical studies.Discrepancy situations were resolved by consensus.

Outcomes
Primary outcome variables were "postoperative complications", dichotomized in yes or no, classifying its according to Clavien & Dindo's proposal [20], and "hospital mortality", dichotomized in yes or no.Secondary outcome variables were year of publication, geographical origin of the studies, designs of primary studies, number of patients considered in each study, main clinical manifestation, anatomical location and type of cyst, hospital stay, a surgical procedure performed, reinterventions, and a different kind of associated therapeutics.

Statistics
Descriptive statistics was applied with calculation of frequencies, averages, standard deviations and weighted averages.

Additional analyses
Meta-analysis was performed comparing the behavior of the variables under study in two periods of time (1982-2006, period A vs. 2007-2023, period B), applying a weighted least squares regression model (the weights were the number of patients of each scientific article).Methodological quality of primary studies was determined applying MInCir scales for therapeutic procedures and prognosis [21,22].Dichotomization was decided because during the exploratory analysis of the data, we verified that this point divided the sample under study into two equal parts.Both used scales for determine methodologic quality (MQ), are valid (face and content validity, and construct validity for extreme groups) and reliable (interobserver reliability).

Search strategies
Trip Database (n = 4) (echinococcosis OR "cystic echinococcosis" OR hydatidos* OR "echinococcus granulosus infection*" OR "infection*, echinococcus granulosus" OR "hepatic hydatid cyst" OR "liver hydatid cyst" OR "liver hydatidosis" OR "hepatic hydatidosis"), (cholangit* OR cholangiohydatidosis), ("hospital mortality" OR mortality OR "postoperative complications") MInCir-T scale, composed of 3 domains and 6 items: the first related to the study design; the second to the population sample size, and the third related to the methodology used; according to which, a score which represents the sum of the 3 domains is generated, with a final score that can vary between 6 and 36 points (6 points being the worst MQ study and 36 being the best), with a cut-off point to define the construct of 18 points [21].And MInCir-P scale, composed of 4 domains and 11 items (study design, population sample size, methodology used, analysis and conclusions); according to which, a score which represents the sum of the 4 domains is generated, with a final score that can vary between 7 and 60 points (7 points being the worst MQ study and 60 being the best), with a cut-off point to define the construct of 33 points [22].Then data were entered to a spreadsheet and calculation of weighted means was applied, and its comparison applying a weighted least squares regression model (Fig 2).

Risk of bias in individual studies
The likelihood of inaccuracy in the estimate of causal effect in primary studies was assess applying MInCir scales [21,22], in both time periods.

Ethics
In order to reduce selection and analysis biases masking of authors and study centers was implemented.

Study selection
357 studies were retrieved from the search, and 89 were obtained from cross-searches.Of these, 446 articles, 201 were eliminated due to duplication of information sources.245 were

Study characteristics
39.2% of the included studies were published in the last decade (Table 2).Turkey had the highest number of publications (n = 29, 28.4%; Table 3).Most included studies were case reports and case series (64.7% and 33.3% respectively [Table 4]), representing 1241 patients, with a weighted mean age of 43.7 years, 50.6% male (Table 5).

Synthesis of results
Weighted means of the common bile duct and cyst diameter were 16.3 mm and 12.9 cm, respectively (Table 5).Clinical presentation was obstructive jaundice, acute suppurative  cholangitis, acute pancreatitis and a mixture of cholangitis with acute pancreatitis.In the common bile duct, daughter vesicles and germinative membrane were found.CE2 and CE3B were the most frequent types founded (Table 4).CH most frequent treatment was choledocostomy with a Kehr tube, and hydatid cyst's most common treatment was partial cystectomy.Associated pharmacotherapy with benzimidazoles and antibiotics was utilized (Tables 5 and 6).With a weighted mean of 14.4 days of hospital stance, it was verified that 26.2% of patients developed postoperative complications (74.3% Clavien and Dindo III and IV), 6.7% needed re-interventions, and 3.7% died (Table 5).The etiology and Clavien & Dindo distribution of postoperative complications is summarized in Table 6.
MQ of primary studies was 9.6±1.1 applying MInCir-Therapy scale (minimum 8 and maximum 15 points), and 14.5±4.3applying MInCir-Prognosis scale (minimum 13 and maximum 53 points).When measuring methodological quality in the time periods under study, no statistical differences were observed (Table 5).Thus, the likelihood of inaccuracy in the estimate of causal effect in primary studies is high.
Finally, when comparing different in-study variables in two different time-periods, statistical difference in total leukocytes (p = 0.0163) and common bile duct diameter (p = 0.001) was observed.However, no differences were verified in postoperative complications, re-interventions or hospital mortality (Table 5).

Possible biases in the review process
Additional information was requested from the authors to expand or verify some study data, unfortunately there was no response.Therefore, missing data may introduce bias in this review.The risk of missing studies was reduced by searching for cross references.

Risk of bias between studies
There may be publication bias, given the concentration of studies from a few countries, and the paucity of studies from other geographic areas, places, and countries (Table 3).

Summary of the evidence
This is the first SR that summarizes the available evidence concerning CH.There are one SR refers to gallbladder echinococcosis, based on 20 studies that include 22 cases [119].The information of this SR was recovered from systematic searches carried out in 7 information sources (metasearch engines, libraries, and databases), including information of the last 40 years, and represents a compilation of 102 primary articles that represent 1241 patients treated in different countries, but preferably in Turkey, Greece, Morocco, and Spain.The first drawback of the selection of MeSH terms and free words in order to define the search strategies, was the need to highlight that the CH concept is either unclear or is generally not well-known given that the number of publications found where CH appears in the title or abstract, is extremely limited (only 5 primary studies in this SR).
Most primary articles with which we worked had other types of denominations, such as "frank biliary communication", "frank intrabiliary rupture", "frank cysto-biliary communication", "ruptured liver hydatid cyst", "opening in the biliary tract", "complicated hepatic hydatid disease", etc., articulated with the concept "role of ERCP".Considering such, it is important to note that all these concepts, only define the existence of communications between a hydatid cyst and the bile duct, but do not consider necessarily the presence of hydatid material (daughter vesicles, germinal membrane, or a part thereof), inside the biliary tree.On the other hand, the use of different definitions for the same concept may represent a source of selection and information biases.
It was very interesting to note that in two different time periods, the variables of postoperative complications, re-interventions and hospital mortality showed very similar behavior, though without statistically significant differences.Consequently, it could be purported that the need for re-interventions, the morbidity and mortality associated with CH have not changed despite continuous advancements in technology, suggesting that CH is an aggressive disease itself.
In patients with sepsis due to cholangitis secondary to CH, who require emergency surgery, taking the patient directly to the operating room would seem indicated to repair the cysto-biliary communication, without previous ERCP, given that ERCP is an invasive procedure that should be performed by an experienced team, which is not always on site or available in emergency centers around the world [23].On the other hand, is possible that type of cyst and or size has impact on the development of CH.For example, CE2 or CE3B type, has a higher rate of CH based on findings in bile duct (daughter vesicle and germinate membrane + daughter vesicle, reach 70.6%, because daughter cysts were present only in CE2 and CE3B).So, I it is possible could be a relationship between cyst size and/or type of cyst with CH.
Moreover, the variables that were found to be associated with the development of postoperative complications were as follows: common bile duct diameter (weighted average of 16.6 mm), main cyst diameter (weighted average of 13.2 cm), leukocytosis (weighted average of 13,469 10e3/uL), total bilirubin (weighted average of 5.5 mg/dL), alkaline phosphatase (weighted average of 799 U/L), and transaminases (weighted averages of 296 and 335 U/L).
In addition, the variables that were found to be associated with mortality were: common bile duct diameter (weighted average of 18.7 mm), main cyst diameter (weighted average of 13.8 cm), leukocytosis (weighted average of 14,546 10e3/uL), total bilirubin (weighted average of 4.8 mg/dL), alkaline phosphatase (weighted average of 621 U/L), and transaminases (weighted averages of 200 and 255 U/L).
We devised an alternative methodology for meta-analyzing data derived from studies of different design studies (especially in systematic reviews in which series of cases are the most frequent design founded in the searches).This approach involves the utilization of weighted averages, with weights assigned based on the methodological quality of the studies contributing to each datum [24].

Limitations
The available evidence on CH was obtained only from level 4 studies (case reports, retrospective case series and historical cohorts, with reduced casuistry).On the other hand, methodological quality of primary studies was low: 9.6±1.1 for MInCir-Therapy and 14.5±4.3 for MInCir-Prognosis scales, which cutoff-points are 18 and 33 respectively [21,22].

Conclusion
The available evidence related with CH is indicative that this evolutionary complication of EHQ is prone to severe postoperative complications, the need of reinterventions, and high hospital mortality rates, despite the passage of time.

Table 5 . Clinical characteristics of patients and studies, and behavior of some variables in the two evaluated periods of time.
ASAT: aspartate aminotransferase ALAT: alanine aminotransferase MQ: Methodological quality https://doi.org/10.1371/journal.pntd.0011558.t005