Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks

Introduction

Hepatobiliary diseases are a significant and longstanding medical challenge, with documentation extending as far back as 2000 BC, to reports of modern-day gallstones in Egyptian mummies (1). Since these first records, the field of hepato-pancreato-biliary (HPB) surgery (which involves the treatment of diseases found in the gall bladder, pancreas, liver, and bile ducts), has evolved massively (2). Nonetheless, complications may still arise, which carry significant consequences for patients, healthcare providers, and medical systems alike.

HPB procedures can be performed through an open procedure or laparoscopically, while the robotic approach is still being developed (3). These procedures include cholecystectomy, distal and total pancreatectomy, partial hepatectomy, total hepatectomy or liver transplants, pancreaticoduodenectomy (Whipple), and cholecystectomy (3).

There are many postoperative complications associated with HPB surgeries. One of the major complications arising from HPB surgery is anastomotic leaks (ALs). This includes postoperative pancreatic fistula (POPF), referring to the leakage of pancreatic fluid, and bile leak (BL) which refers to leakage of biliary contents. Major hospital centers have mortality rates associated with pancreatic AL under 5%, however, the morbidity remains high, at 30–50% (4,5). Hepatic surgeries may lead to BLs which occur in nearly 3.6–12.9% of cases after liver resection (6-12). Therefore, ALs are a major cause of concern, often increasing patient length of stay (LOS), and treatment cost, while lowering quality of life (4-7).

This narrative review provides a thorough synthesis of the latest advances in HPB surgery, in the context of ALs. Here, we focus on background information related to defining and classifying leaks, as well as the burden associated with the occurrence of leakage.

Terminology

This narrative review features a number of important acronyms, whose definitions are essential in understanding the context of the results presented here. As such, Table 1 is included at the beginning of this paper, as an accessible reference for the various acronyms and definitions used throughout the results and discussion to come. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-9/rc).

Methods

The most recent evidence from various databases was used to inform this narrative review, including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Literature searches were performed using the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). No restrictions were placed on article type, except that articles must have been published in English or have an English translation. Inclusion was determined by the authors and their collaborators (see acknowledgements), aiming to include a broad, unbiased, and comprehensive range of relevant studies, including recent publications. Table 2 summarizes the search strategy used for this narrative review. Figure S1 provides a more detailed flow-chart of the search strategy, using one database (PubMed) as an example.

Findings

POPF

Following a pancreatic procedure, an abnormal connection between the pancreatic ductal epithelium and another epithelial surface, such as the peri-pancreatic space or the peritoneal cavity, may be established, due to a disruption of the pancreatic duct (13). The collection of pancreatic fluid that has leaked into another cavity due to pancreatic duct disruption—termed ‘pancreatic leak’ or POPF allows pancreatic digestive enzymes to leak out of the pancreatic ductal system, disrupting other epithelial surfaces. POPF can significantly increase patient morbidity, with pain, ileus, fever, higher probability of abscess formation, and potential onset of sepsis and hemorrhages ultimately increasing hospital stay, and leading to poorer patient outcomes (13,14). Pancreatic enzymes erode the surrounding tissue, forming a pathway between the disrupted duct, and the connected epithelial surface (13).

The incidence rate of leakages varies depending on the type of surgery performed, with Whipple procedures and pancreatectomies having incidence rates of approximately 13% and 31%, respectively (14). The mortality rate of secondary complications associated with POPF can be as high as 40% (14). The high morbidity and mortality rates seen in POPF patients stems from the additional complications that arise due to the fistula, such as abdominal hemorrhages and abscesses, postoperative bleeding, and multiorgan failure (15). Major complications associated with pancreatic fistulas can be split into two broad categories: hemorrhage and sepsis. Both play a role in the development of additional consequences, including prolonged hospital stays, delayed gastric emptying (DGE), enteric fistulae, multiorgan failure, and death (16).

Moreover, patients who develop POPF are more likely to be impacted by additional complications, including wound infection; acute cardiac events; pulmonary, renal, thromboembolic, and septic complications; BLs; and intra-abdominal abscesses (16). POPF has also been linked to the development of DGE following Whipple procedures, resulting in poor nutritional outcomes which may further lengthen hospital stays (16).

A number of risk factors have been associated with POPF, including age >60 years, obesity, smoking, length of operation, pancreatic texture (soft—high risk), and pancreatic duct diameter (17-22). Body mass index (BMI) is a strong predictor of the risk of POPF, with increasing BMI significantly associated with exponentially increased POPF risk. This is due in part to the texture of the pancreas, which is majorly influenced by BMI. Overweight or obese patients with BMI ≥25 kg/m² have greater adipose deposits within the pancreas that contribute to the softer texture (20). This, in turn, leaves the pancreas friable and unable to effectively hold stitches from the anastomosis—providing the opportunity for fluid to leak out of the pancreas and cause POPF. BMI ≥30 kg/m² has been more predictive of clinically relevant POPF than BMIs over 25 kg/m². In addition, BMI ≥35 kg/m² is strongly associated with an increased development of DGE (20). Smoking is a modifiable risk factor that is debated and poorly understood, believed to result in ischemia and microvascular damage of small areas around the pancreatic anastomosis (18). This may slow down healing and increase risk of POPF. Several retrospective studies have found smoking as a risk factor on univariate analysis, although statistical significance from multivariate analysis remains mixed (18,23,24). The length and complexity of surgical procedures has been shown to be a risk factor not only for POPF, but as will be discussed below, BLs as well. Long, complicated surgeries, as well as those that are open or invasive all increase risk (24).

Other risk factors, such as blood pressure, alcohol consumption, and American Society of Anesthesiologists (ASA) score have been explored, but at this time provide less conclusive evidence than those described above, which based on current literature are the strongest predictors of POPF (25,26).

2005 International Study Group of Pancreatic Fistula (ISGPF) definition

Up until 2005, a commonly agreed upon definition of POPF was absent from literature. This led to conflicting opinions on grading, classification, and valuable comparison of leaks (27). For example, prior to the introduction of the commonly agreed on system, a leak could be graded based on many parameters, such as daily output and duration of the fistula, with a 2005 study identifying a striking 26 definitions of POPF in the literature (27). These variations in criteria, and multiple definitions and categorizations of pancreatic leaks created challenges in comparing surgical outcomes and patient/healthcare provider experiences.

In 2005, a panel of pancreatic surgeons came together as part of the ISGPF to properly define pancreatic leaks and produce a grading system for leak classification (27-29). POPF was defined as “an abnormal communication between the pancreatic ductal epithelium and another epithelial surface containing pancreas-derived, enzyme-rich fluid” (13). The formal diagnostic criteria was defined as “output via an operatively or a subsequently placed drain, of any measurable volume of drain fluid on or after postoperative day three, with an amylase content greater than three times the upper normal serum value” (27). Elaborating on this, a description of the appearance of drain fluid following the development of the leak, with a clear description of a range of colors the fluid may take was added. This ranged from a dark brown to greenish bilious fluid to a milky water to clear “spring water” like fluid that looks like pancreatic juice (27). The team also included several common signs of leaks that could be detected in patients, such as abdominal pain and distention, with impaired bowel function, DGE, fever, serum leukocyte count greater than 10,000 cells/mm³ and increased C-reactive protein (CRP) (27). Despite progress made in defining leaks, the team feared that such a broad definition may be too inclusive, such that asymptomatic patients could fit in the definition of a POPF. These patients may not have a leak or be clinically ill, hence a grading system was proposed to properly classify types of leaks—including those which may be subclinical (27).

A three-class grading system was created, ranging from A to C to describe the pancreatic fistulae, with A being the least severe and C being the most severe (28). A Grade A leak was distinguished through elevated amylase in the drain fluid. Grade B leakage was identified by the need for modified postoperative management, such as use of antibiotics. Grade C leak was classified as those requiring severe departure from regular postoperative management, with the need for reoperation, or percutaneous drainage to manage the leak (28). For the next 11 years, the proposed system of classifying leaks became the standard system used by surgeons worldwide. Over time, a number of surgeons noted limitations with the system. In 2016, the system was revised by the ISGPF, now known as the International Study Group in Pancreatic Surgery (ISGPS) (27,28).

Limitations of original leak grading system

• Inclusion of Grade A leaks within the POPF definition as a postoperative complication. Grade A leak patients have a relatively uncomplicated recovery, and do not require changes to the patient’s clinical management (28).
• Unclear distinction between Grade B and C leaks, and their associated inclusion criteria in the original paper (28). The use of percutaneous drainage was used to identify Grade C leaks in the paper, however the associated summary table listed it as a potential Grade B procedure. Therefore, subsequent classifications were based on different interpretations.
• Medical professionals were concerned regarding the conversion of Grade A leaks into Grade B leaks, especially after the patient had been discharged with the drain (28). This was a common occurrence at the time in patients who underwent distal pancreatectomies and did not experience any symptoms postoperatively.

Hence, the grading system was revised, along with the criteria for diagnosis (Table 3).

Revisions made to diagnosis and classification system

• An increased amylase content in the patient’s abdominal fluid must be associated with another clinically significant condition, that is, it is causally linked with the pancreatic leak, for the diagnosis of a pancreatic leak (31).
• Grade A pancreatic leaks no longer existed under the revised system, and were termed as biochemical fistulas or biochemical leaks, which became a new asymptomatic pancreatic leak category (31).
• A greater distinction between Grade B and C leaks was established. Grade B leak diagnosis was modified to include some invasive procedures including percutaneous or endoscopic drainage, and angiographic procedure. A Grade C leak was characterized and limited to a subset of patients that developed a severe life-threatening condition such as organ failure that required a reoperation or died due to the leakage (31). ISGSP defined organ failure as follows: “the need for reintubation, hemodialysis, and/or use of inotropic agents for >24 hours because of respiratory, renal, or cardiac insufficiency respectively” (31).

This narrative review uses the updated version of the grading system proposed in 2016.

New classification of pancreatic leaks (2016)

The ISGPS defines a POPF as an output via an operatively or a subsequently placed drain, of any measurable volume of drain fluid on or after postoperative day three, with an amylase content greater than three times the upper normal serum value (27,31).

BL

BLs refer to the leakage of bile from the biliary tree, cut surface of remnant liver, or from a hepatoenteric anastomosis into the abdomen (32). Leaks formed from the cut surface of the remnant liver are referred to as peripheral BLs, while those that originate from the bile ducts are known as central BLs (33). BL can facilitate abnormal connections of the gallbladder with the biliary tree, and sometimes may even involve the GI tract (34). An abnormal connection involving the GI tract is known as an internal fistula, while a connection with the abdominal wall represents an external fistula (34).

The causes of the BL formation can vary depending on the type of surgical procedure. Following cholecystectomy, BL can be caused due to improper ligation of the cystic duct or accessory ducts, allowing the ligature to slip and come loose (35). In the case of hepatectomies, BL usually originates from the biliary anastomotic site, which can be caused by the dislodgement or removal of an external drainage tube, or iatrogenic bile duct injury (BDI) (35). In some cases, BLs can also occur following pancreatic surgeries. Similar to a cholecystectomy or hepatectomy, the cause of BL is mainly due to BDI, or in some cases leakage from a bilioenteric anastomosis, if one was created (36-42).

The reported incidence rates of BL following a cholecystectomy are relatively low at 0.3–2.7%. Hepatectomy patients have an incidence rate of 4.8–7.6% (37,42-45), and pancreatic patients who do not undergo iatrogenic biliary injury have an incidence rate of 2–10% (36-41), however if injury occurs the incidence rate rises to 24% (36,41,46).

Once a BL forms, the bile can seep from the injured duct or cut remnant liver and form distinct bile collections in the surrounding areas known as bilomas (47). This causes an inflammatory reaction and fibrosis in the area of the deposition (47). Left untreated, bilomas become an excellent medium for the proliferation of bacteria, owing to the mixture of bile, blood and devitalized tissues in the area surrounding the resected liver. Bacterial proliferation can impair the normal host defense mechanism, allowing sepsis development (37,43). This outcome is extremely dangerous for hepatectomy patients as septic conditions around the liver and reduction in liver volume can lead to liver failure (43). Additionally, BL can lead to peritonitis, multiple organ dysfunction syndrome, cholangitis, liver abscesses, and several other postoperative complications. These secondary complications contribute to the associated 5% mortality rate, as well as longer hospital stays and increased medical bills (44,45).

As with POPF, several strong risk factors/predictors of BL have emerged in the literature. These include BMI and nutritional status, operation duration, diabetes, and neoadjuvant chemoradiotherapy (24,48-51). With BMI an important indicator of a patient’s nutritional status, patient BMIs <20 kg/m² have emerged as a risk factor for BL. For instance, in cancer patients, malnutrition is closely associated with the incidence of postoperative complications, length of hospital stay, and increased mortality, supporting findings that low BMI is a risk factor associated with BL (48). Diabetes increases the risk post-operative infections and mortality, with impacts on microcirculation disorders that can prevent/impact proper healing (49). The pathophysiology of diabetes also results in damage to the residual liver, increasing the risk of postoperative BLs. In line with this, it is recommended that pre-operative blood glucose control be emphasized in order to manage the impact of diabetes on overall patient recovery, including minimizing risk of BLs (49). For patients undergoing neoadjuvant therapy, particularly chemotherapy, this too has been noted as an important risk factor (50). Healing is negatively impacted by damage to the liver that makes it soft and fragile, increasing the risk of leaks. This was found to be most impactful when treatment was within 4 weeks of surgery, leading to more Grade A and Grade B leaks, with little effect on Grade C (see below for a description of leak grades) (50). As described above for POPF, operation duration is a risk factor for similar reasons in patients who go on to experience BLs (including complexity of surgery and invasiveness of procedure).

Definition

Prior to 2008, several definitions of BL existed, which provided a wide range of cutoffs for the volume of drain fluid and concentration of bilirubin within the drain fluid. In 2008, the International Study Group for Liver Surgery (ISGLS) proposed a system of diagnosis and grading for BLs (52).

BL was defined as “fluid with an elevated bilirubin level in the abdominal drain or intra-abdominal fluid on or after post-operative day three or the need for radiological intervention, owing to biliary collections or re-laparotomy due to biliary peritonitis” (52).

Elevated bilirubin concentration is defined as “a bilirubin concentration at least three times higher than the serum bilirubin level measured at the same time” (52). Additionally, a system of leak classification was developed, as is described in Table 4.

Postoperative consequences of leaks

Pancreatic leaks

Table 5 provides a summary of consequences experienced by patients with POPF, as well as burdens placed on healthcare systems as a whole.

BL

Table 6 provides a summary of postoperative consequences experienced by patients following development of BL. As the literature currently stands, the impact of BL on clinical and economic outcomes is less studied than that of POPF. However, it is clear that the development of a BL leads to increased costs, and poorer outcomes for patients.

Conclusions

Despite the ongoing progress in clinical medicine, addressing ALs in the context of HPB procedures remains a formidable challenge. A universally accepted grading system is yet to be established, but significant strides have been taken to conceptualize and define leaks of varying severity. Understanding these grading systems is crucial in both clinical and research settings, as issues in accurate identification and classification of leaks pose major limitations for diagnosis, incidence estimates, and proper patient categorization in research analyses.

Beyond diagnostic challenges, the gravity of leaks cannot be overstated. Marked by high morbidity and mortality, an increased rate of secondary postoperative complications, elevated reoperation rates, and prolonged hospital stays, the burdens extend not only to patients experiencing POPF or BL, but also impact their healthcare teams and broader medical system. The urgent need to alleviate these serious consequences underscores the necessity for further research in this domain. Recognizing that ALs persist as a reality in HPB surgical procedures, there is a compelling call to focus on exploring strategies for early detection—and consequently, treatment—of this severe and potentially life-threatening complication.

Acknowledgments

Funding: This research was funded in full by FluidAI Medical.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-9/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-9/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-9/coif). O.R. is a full-time permanent employee of FluidAI Medical, a medical device company that works on early prediction of postoperative complications, including anastomotic leaks. The company contributes to research associated with this manuscript in the following ways: clinical interest in the topic of this manuscript; attendance at conferences/educational events related to this article’s content, travel related to this article’s content, and stock options with the company. M.S. is a full-time permanent employee of FluidAI Medical, a medical device company that works on early prediction of postoperative complications, including anastomotic leaks. The author holds clinical interest and professional expertise in the topics explored within this article. The author also attends meetings/travel related to content in this article through their role at FluidAI Medical, and owns stock options with the company. N.H. is a full-time employee at FluidAI Medical which focuses on the early predication of leaks after gastrointestinal surgery. The author’s role at FluidAI involves expertise in the topics explored within this article. The author also holds stock options with FluidAI. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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