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Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Shang Yu Wang , Chun Nan Yeh
, Yi Yin Jan
, Miin Fu Chen
Correspondence to: Chun Nan Yeh
ORCID https://orcid.org/0000-0003-1455-092X
E-mail yehchunnan@gmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2021;15(4):517-527. https://doi.org/10.5009/gnl20052
Published online September 15, 2020, Published date July 15, 2021
Copyright © Gut and Liver.
Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.
Keywords: Gallbladder stone, Cholelithiasis, Cirrhosis, Cholecystectomy, Laparoscopy
Cirrhosis is one of the most complex human diseases and causes significant physiological changes, local anatomical alterations, immune status modifications, and other associated risks, which influence the life expectancy of patients. Cholelithiasis, a common medical condition, has been recognized to have a higher incidence in cirrhotic patients than in the general population.1 Currently, surgical treatments, laparoscopic cholecystectomy (LC) or open cholecystectomy (OC) via laparotomy are the standard of care for symptomatic gallbladder stones (GB stones), including cases with repeated episodes of pain, gallbladder polypoid lesions, choledocholithiasis with or without cholangitis, acute cholecystitis, and biliary pancreatitis. Without definite surgical treatment, the incidence of symptom relapse is high.2
Regarding surgical treatment for symptomatic GB stones in patients with cirrhosis, there are additional issues that should specifically be considered: (1) Should the surgical indication be modified? (2) Do we have any strategy to tackle the surgical difficulty that is increased in relation to local conditions such as the presence of abundant collateral vessels around the surgical field? (3) Similarly, how can we manage perioperative complications and improve surgical outcomes? In this review, we first summarize the pathophysiology of cholelithiasis in cirrhotic patients. Then, a thorough review of several relevant surgical issues, including surgical indications, surgical risks, surgical procedures, and surgical outcomes, is presented. Finally, we propose a suggested treatment flowchart for cirrhotic patients with symptomatic GB stones.
Cholelithiasis is a common condition in the general population. The prevalence of cholelithiasis is approximately 10% to 20%, while symptomatic cholelithiasis occurs in approximately 20% of individuals with cholelithiasis.3 Cirrhotic patients, however, have been demonstrated to have a higher prevalence of cholelithiasis.4,5 In addition, the cumulative incidence has also been proven to be correlated with the course of cirrhosis progression, and this phenomenon reveals that a greater severity and a longer duration of cirrhosis increase the risk of cholelithiasis.1,6 Sheen and Liaw5 reported a Taiwanese cohort of healthy persons and chronic hepatitis B patients with or without cirrhosis (933 vs 500). According to their results, the prevalence of GB stones in cirrhotic patients was 4 to 5.5 times higher than that of healthy persons. In addition, the prevalence of GB stones increased along with increasing duration and severity of chronic liver diseases, with good linear correlation. In cirrhotic patients, the formation of black pigment stones surpassed that of cholesterol stones. Coelho
Although the etiologies of cirrhosis, such as chronic viral hepatitis C and alcoholism, may increase lithogenesis,1,8 the deterioration of hepatic function in cirrhotic patients changes the biochemical environment of bile and, combined with other physiological changes, is the major causative factor, especially for black stones (Fig. 1). In cirrhotic patients, the compositions of secreted bile are changed, including decreased conjugated bilirubin, decreased phospholipid and bile acid production, and increased glycoprotein levels.3,6 The changes in bile composition enhance the nucleation of biliary stones. In addition, hemolysis is also an important contributor, and this coincides with the fact that black pigmented stones are the major type of stones found in cirrhotic patients. While portal hypertension-related hypersplenism may increase the destruction of erythrocytes (namely, hemolysis), a change in the cholesterol-to-phospholipid ratio of the erythrocyte membrane due to impaired hepatic function can alter the physiology, flexibility, and morphology of erythrocytes, increasing their destruction.9 Other factors, such as hypomotility of the gallbladder and increased enterohepatic circulation of unconjugated bilirubin, have also been proposed. The change in gallbladder motility has been confirmed by serial real-time ultrasonography and dynamic studies of gallbladder motility, and the extent of gallbladder smooth-muscle dysfunction has also been proven to be correlated with the severity of cirrhosis.10-12 Although the underlying mechanism is not well established, the observation of impaired motility of the gallbladder has been recognized to be a risk factor for cholelithiasis in cirrhotic patients based on currently published studies.10-12 Enterohepatic circulation occurs in the bowel segment of the distal ileum, and this physiologic process mainly facilitates bile acid absorption.13 Over 90% to 95% of secreted bile acid will be absorbed into the portal venous system and subsequently resecreted into bile.14 While alcoholism is one of the major etiologies of cirrhosis, alcohol consumption can also impair the absorption of bile acid, and this phenomenon further increases the bile acid concentration in the gastrointestinal tract.15,16 Intraluminal bile acid will increase the solubility of unconjugated bilirubin, further boost the absorption of bilirubin into the portal venous system, increase bilirubin secretion from the liver, and then heighten the risk of cholelithiasis.16 In summary, cirrhosis can influence the homeostasis of several physiological processes, and all these changes promote cholelithiasis in cirrhotic patients from different aspects.
Most of the studies relevant to cholecystectomy in cirrhotic patients can be categorized into two periods: the pre-LC era and the LC era. The cutoff point is 1987.17 In this article, we extensively review the relevant studies. We focus on surgical indications, procedures, outcomes, and special perspectives related to cholecystectomy in cirrhotic patients. The relevant primary studies after 2000 are summarized in Table 1.
Table 1 Summary of Relevant Studies Regarding Cholecystectomy for Cirrhotic Patients after 2000
Author (year) | Study design | Patient numbers (case vs control)* | Morbidity/mortality, % (case vs control) | Conclusions | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
A | B | C | Total | A | B | C | Total | ||||
Fernandes | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 38 | 10 | 0 | 48 vs 187 | NA | NA | NA | 10.4/0 vs 2.1/0 | LC is safe for CTP class A and B cirrhosis. | |
Poggio | Retrospective: cirrhosis+LC vs cirrhosis+OC | 22/17 | 4/7 | 0/0 | 26 vs 24 | NA | NA | NA | 4/0 vs 29/0 | LC is safe for patients with CTP class A and B cirrhosis. There are several advantages over OC, including lower morbidity, shorter operative time, briefer hospital stay, and less transfusion. | |
Clark | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 14 | 9 | 2 | 25 vs 1,275 | 50/0 | 55.6/0 | 50/50 | 52/4 | LC in patients with cirrhosis is associated with significant but acceptable morbidity and mortality rates. | |
Leone | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 19 | 5 | 0 | 24 vs 72 | NA | NA | NA | 20.8/0 vs 9.72/0 | LC is safe for patients with compensated cirrhosis and should be the treatment of choice. | |
Yeh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 193 | 33 | 0 | 226 vs 4,030 | NA | NA | NA | 6.6/0.88 vs 5.3/0.01 | LC is a feasible procedure for most CTP class A and B patients with cholecystolithiasis. | |
Tuech | Retrospective: cirrhosis+LC | 22 | 4 | 0 | 26 | NA | NA | NA | 26.9/0 | LC seems to be safe in selected CTP class A and B patients. | |
Cucinotta | Retrospective: cirrhosis+LC | 12 | 10 | 0 | 22 | NA | NA | NA | 36/0 | LC can be performed safely in selected patients with CTP class A and B cirrhosis. | |
Currò | Retrospective: cirrhosis+LC | 22 | 16 | 4 | 42 | 18/0 | 37.5/0 | 75/50 | 31.0/4.76 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients, but it is a very high-risk procedure in CTP class C patients. | |
Schiff | Retrospective: cirrhosis+LC | NA | NA | 3 | 31 (high risk: 18; intermediate risk: 5; low risk: 8)† | NA | NA | NA | NA | The preoperative degree of coagulopathy instead of the CTP classification predicts the difficulty of LC. | |
da Silveira (2006)44 | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 22 | 11 | 0 | 33 vs 66 | NA | NA | NA | 15.1/0 vs 1.5/0 | LC is a safe and effective alternative to OC in CTP class A and B cirrhotic patients undergoing elective or emergent cholecystectomy. | |
Curro | Retrospective: cirrhosis+LC | 32 | 18 | 0 | 50 | 16/0 | 38/0 | NA | 24/0 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients. | |
Leandros | Retrospective: cirrhosis+LC | 23 | 11 | 0 | 34 | NA | NA | NA | 14.7/2.94 | LC can be carried out in selected patients with well-compensated CTP class A and B liver cirrhosis. | |
Mancero | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 23 | 7 | 0 | 30 vs 60 | 21.6/0 | 57.1/0 | NA | 29.9/0 vs 5/0 | LC may be safely performed in cirrhotic patients. | |
Pavlidis | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 29 | 9 | 0 | 38 vs 1,440 | NA | NA | NA | 7.89/0 vs 1.59/0.13 | LC can be safely performed in CTP class A and B cirrhotic patients with symptomatic gallstone disease. | |
Shaikh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 12 | 8 | 0 | 20 vs 230 | NA | NA | NA | 15.0/0 vs 19.1/0 | LC is an effective and safe treatment for symptomatic gallstone disease in select patients with CTP class A and B cirrhosis. | |
El-Awadi | Prospective: cirrhosis+LC vs cirrhosis+OC | 47/43 | 8/12 | 0/0 | 55 vs 55 | NA | NA | NA | 12.7/0 vs 34.5/0 | Compared with OC, LC offers lower morbidity, a shorter operative time; early resumption of diet with less need for blood transfusion and a reduced hospital stay. | |
Hamad | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 10/10 | 5/5 | 0/0 | 15 vs 15 | NA | NA | NA | 33.4/0 vs 33.4/0 | For CTP class A and B cirrhosis, LC is comparable to OC regarding operative time, morbidity, mortality, and effect on liver function, but with a shorter hospital stay. LC would be the first choice in cirrhotic patients. | |
Lledó | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 26 | 15 | 2 | 43 vs 460 | NA | NA | NA | 37.2/0 vs 6.00/0 | LC is an effective and safe procedure and should be the treatment of choice for symptomatic cholelithiasis or cholecystitis in patients with compensated cirrhosis. | |
Nguyen | Retrospective: cirrhosis+LC | 47 | 19 | 2 | 68 | NA | NA | NA | <7.4/0 | LC in patients with cirrhosis is feasible, with no mortality and low morbidity, especially in patients with CTP class A cirrhosis. |
LC, laparoscopic cholecystectomy; CTP, Child-Turcotte-Pugh; OC, open cholecystectomy; NA, not available.
*The case group comprised cirrhotic patients with intended LC in each study, and the patients were categorized based on the CTP classification; †Risk stratification is defined on the basis of the coagulation function.
For patients with symptomatic cholelithiasis, several interventional procedures, including LC with or without bile duct exploration and endoscopic retrograde cholangiography and pancreatography (ERCP), can be conducted as either single or combined procedures. Since the
For cirrhotic patients with symptoms, the surgical indications of cholecystectomy, especially in the era of LC, have been generally adopted as being similar to those for the general population, except for patients with Child-Turcotte-Pugh (CTP) class C (see the following section).22 In addition, early cholecystectomy should be considered after patients are stabilized because later onset episodes of complications may impose a higher risk on these patients.23,24 Although LC is recognized as a safe procedure under emergency circumstances, even for cirrhotic patients,25 planned and elective LC should be the first choice for symptomatic GB stones.
In the era before LC, OC was the mainstream treatment for symptomatic GB stones, and the outcomes were catastrophic.26,27 In the era of LC, cholecystectomy has become a feasible procedure for cirrhotic patients.28,29 For decades, cirrhotic patients have been recognized as having high surgical risk.29-31 Therefore, preoperative risk stratification for cirrhotic patients is crucial to minimize postoperative complications. Several laboratory parameters32 and scoring systems, including the CTP score and the Model for End-Stage Liver Disease (MELD), have been proposed as risk stratification measures for cirrhotic patients.33-36 The CTP score is the most prevalent tool for preoperative risk stratification. In patients with CTP class C, cholecystectomy is not recommended, and conservative treatment is suggested. Although catastrophic outcomes of OC for CTP class C patients were reported in the 1980s, there have been no case series reporting more than five CTP class C patients undergoing LC-intended procedures. Currò
For CTP classes A and B, LC can be conducted once the surgical indication is justified and meticulous postoperative care is feasible, and most published studies have proven this fact.37,40-50 Nguyen
The MELD score was proposed early in this century and was initially used to predict early death following elective transjugular intrahepatic portosystemic shunts and to help determine organ allocation priorities.51,52 The MELD score is a mathematical model that provides a more accurate prediction power than the CTP does.36 The cutoff value has not yet been established. While a previous retrospective study suggested a MELD score of 13 as a cutoff,36 real-world data published recently by Dolejs
Some laboratory markers, including bilirubin, creatinine, international normalized ratio, and the platelet count, have been proposed as surrogates for preoperative risk stratification.32,33 However, all these factors reflect the severity of hepatic function impairment. In summary, for cirrhotic patients with planned cholecystectomy, precise evaluation of hepatic function is the most important preoperative evaluation in addition to other general preparations. Decompensated liver cirrhosis is the major contraindication for planned cholecystectomy. Surgical treatment for patients with decompensated liver cirrhosis is reserved for life-threatening conditions.
Cholecystectomy has been considered a daunting procedure and can only be performed on cirrhotic patients under “really necessary” conditions.26 In 1985, Bloch
The surgical outcome and safety of LC have been extensively studied compared to the corresponding measures in the general population. Several studies have compared cirrhotic patients with noncirrhotic patients after LC.40,41,44,47,48,62-65 While most of those studies were retrospective, Clark
For cirrhotic patients, liver transplantation is always an option of treatment. Any abdominal surgery, especially hepatobiliary surgery, performed before transplantation may induce peritoneal adhesions, which in turn may increase the difficulty of future transplantation surgery. Polymeneas
The original idea of subtotal cholecystectomy can be traced back to the 19th century.67 In the 1950s, Madding68 suggested that subtotal cholecystectomy could be an alternative to conventional “total cholecystectomy” under circumstances of a difficult cholecystectomy and may be superior to complete cholecystectomy (constrainedly) and cholecystostomy.69 For difficult gallbladders, subtotal cholecystectomy performed by laparoscopy also yields better immediate outcomes with less bile leakage, as reported in a systematic review by Elshaer
Similar to previous studies before the 21st century, Tokyo Guidelines 2018 (TG18), which is based on two systematic reviews, has suggested that subtotal cholecystectomy be considered for difficult situations as a bail-out procedure to avoid serious damage to the bile duct or blood vessels.70-72 Regarding the timing of the publication of TG18, several relevant series related to subtotal cholecystectomy have also been published.73-75 While subtotal cholecystectomy has been recognized as a safe and alternative procedure for total cholecystectomy, the long-term outcome of patients is associated with the presence of retained stones in gallbladder remnants. The rate of retained stones varies from 4% to 15%.70,74 Although most retained stones can be retrieved by ERCP,73 some patients still have to undergo reoperations.75 In general, the rate of long-term complications after subtotal cholecystectomy is higher than that after total cholecystectomy. However, for patients who can “only” undergo subtotal cholecystectomy because of the local condition of the hepatocystic triangle, laparoscopic surgery provides better outcomes than open approach.70
For cirrhotic patients, portal hypertension-associated variceal vessels and a bleeding tendency interfere with the performance of surgery. If good exposure of the hepatocystic triangle cannot be achieved, subtotal cholecystectomy under laparoscopy would be an alternative choice that might prevent patients from experiencing iatrogenic biliary injury, although possible long-term complications should be considered.
Portal hypertension-associated regional anatomic change, variceal vessels, and bleeding tendency may make cholecystectomy even more difficult. Several adjuncts have been applied in various fields of surgery. Several studies related to the application of harmonic scalpels in LC for cirrhotic patients have been published. While some studies revealed that harmonic scalpels may provide benefits with shorter operation times, less blood loss, and even fewer intraoperative GB ruptures,76,77 there was still one investigation that reported no significant benefit from harmonic scalpel use.78 Since all these studies were small in scale, these results might not be convincing. In addition, major complications after LC in the general population are low and acceptable in selected cirrhotic patients. To determine the significant difference under this circumstance, a study with an appropriate sample size would be necessary. In addition, the technique of using energy devices between different surgeons is variable, and this fact cannot be estimated in the aforementioned studies. Further investigation is necessary for this issue. In addition to energy devices, the application of other hemostatic adjuncts, such as oxidized regenerated cellulose and Floseal® (Baxter International, Inc., Deerfield, IL, USA) hemostatic matrix, has also been proposed in LC with positive impact.79,80
Although most of the current evidence recommends LC as a treatment for symptomatic cholelithiasis in cirrhotic patients without decompensation, we can see several pitfalls in all of the relevant studies listed in Table 1: (1) the majority of studies were retrospective; (2) most of the studies enrolled patients with CTP classes A and B; (3) most of the studies presented pooled results instead of subgroup analysis; and (4) the definitions of complications varied from study to study. While de Goede
Based on currently available evidence, we propose a flow chart for the management of cirrhotic patients with GB stones (Fig. 2).81,82 The prevalence of cholelithiasis is relatively high in cirrhotic patients, and the surgical indications for LC in these patients are the same as those for noncirrhotic patients. Once the surgical indication is justified, meticulous preoperative evaluation is crucial. Advanced cirrhosis, such as CTP class C, is the contraindication for surgery. LC is the procedure of choice, just as for the general population. Postoperative management is also particularly important due to the relatively high, although acceptable, rate of complications.
We would like to thank the Chang Gung Memorial Hospital for supporting our research (CMRPG3D0281).
No potential conflict of interest relevant to this article was reported.
Gut and Liver 2021; 15(4): 517-527
Published online July 15, 2021 https://doi.org/10.5009/gnl20052
Copyright © Gut and Liver.
Shang Yu Wang , Chun Nan Yeh
, Yi Yin Jan
, Miin Fu Chen
Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
Correspondence to:Chun Nan Yeh
ORCID https://orcid.org/0000-0003-1455-092X
E-mail yehchunnan@gmail.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.
Keywords: Gallbladder stone, Cholelithiasis, Cirrhosis, Cholecystectomy, Laparoscopy
Cirrhosis is one of the most complex human diseases and causes significant physiological changes, local anatomical alterations, immune status modifications, and other associated risks, which influence the life expectancy of patients. Cholelithiasis, a common medical condition, has been recognized to have a higher incidence in cirrhotic patients than in the general population.1 Currently, surgical treatments, laparoscopic cholecystectomy (LC) or open cholecystectomy (OC) via laparotomy are the standard of care for symptomatic gallbladder stones (GB stones), including cases with repeated episodes of pain, gallbladder polypoid lesions, choledocholithiasis with or without cholangitis, acute cholecystitis, and biliary pancreatitis. Without definite surgical treatment, the incidence of symptom relapse is high.2
Regarding surgical treatment for symptomatic GB stones in patients with cirrhosis, there are additional issues that should specifically be considered: (1) Should the surgical indication be modified? (2) Do we have any strategy to tackle the surgical difficulty that is increased in relation to local conditions such as the presence of abundant collateral vessels around the surgical field? (3) Similarly, how can we manage perioperative complications and improve surgical outcomes? In this review, we first summarize the pathophysiology of cholelithiasis in cirrhotic patients. Then, a thorough review of several relevant surgical issues, including surgical indications, surgical risks, surgical procedures, and surgical outcomes, is presented. Finally, we propose a suggested treatment flowchart for cirrhotic patients with symptomatic GB stones.
Cholelithiasis is a common condition in the general population. The prevalence of cholelithiasis is approximately 10% to 20%, while symptomatic cholelithiasis occurs in approximately 20% of individuals with cholelithiasis.3 Cirrhotic patients, however, have been demonstrated to have a higher prevalence of cholelithiasis.4,5 In addition, the cumulative incidence has also been proven to be correlated with the course of cirrhosis progression, and this phenomenon reveals that a greater severity and a longer duration of cirrhosis increase the risk of cholelithiasis.1,6 Sheen and Liaw5 reported a Taiwanese cohort of healthy persons and chronic hepatitis B patients with or without cirrhosis (933 vs 500). According to their results, the prevalence of GB stones in cirrhotic patients was 4 to 5.5 times higher than that of healthy persons. In addition, the prevalence of GB stones increased along with increasing duration and severity of chronic liver diseases, with good linear correlation. In cirrhotic patients, the formation of black pigment stones surpassed that of cholesterol stones. Coelho
Although the etiologies of cirrhosis, such as chronic viral hepatitis C and alcoholism, may increase lithogenesis,1,8 the deterioration of hepatic function in cirrhotic patients changes the biochemical environment of bile and, combined with other physiological changes, is the major causative factor, especially for black stones (Fig. 1). In cirrhotic patients, the compositions of secreted bile are changed, including decreased conjugated bilirubin, decreased phospholipid and bile acid production, and increased glycoprotein levels.3,6 The changes in bile composition enhance the nucleation of biliary stones. In addition, hemolysis is also an important contributor, and this coincides with the fact that black pigmented stones are the major type of stones found in cirrhotic patients. While portal hypertension-related hypersplenism may increase the destruction of erythrocytes (namely, hemolysis), a change in the cholesterol-to-phospholipid ratio of the erythrocyte membrane due to impaired hepatic function can alter the physiology, flexibility, and morphology of erythrocytes, increasing their destruction.9 Other factors, such as hypomotility of the gallbladder and increased enterohepatic circulation of unconjugated bilirubin, have also been proposed. The change in gallbladder motility has been confirmed by serial real-time ultrasonography and dynamic studies of gallbladder motility, and the extent of gallbladder smooth-muscle dysfunction has also been proven to be correlated with the severity of cirrhosis.10-12 Although the underlying mechanism is not well established, the observation of impaired motility of the gallbladder has been recognized to be a risk factor for cholelithiasis in cirrhotic patients based on currently published studies.10-12 Enterohepatic circulation occurs in the bowel segment of the distal ileum, and this physiologic process mainly facilitates bile acid absorption.13 Over 90% to 95% of secreted bile acid will be absorbed into the portal venous system and subsequently resecreted into bile.14 While alcoholism is one of the major etiologies of cirrhosis, alcohol consumption can also impair the absorption of bile acid, and this phenomenon further increases the bile acid concentration in the gastrointestinal tract.15,16 Intraluminal bile acid will increase the solubility of unconjugated bilirubin, further boost the absorption of bilirubin into the portal venous system, increase bilirubin secretion from the liver, and then heighten the risk of cholelithiasis.16 In summary, cirrhosis can influence the homeostasis of several physiological processes, and all these changes promote cholelithiasis in cirrhotic patients from different aspects.
Most of the studies relevant to cholecystectomy in cirrhotic patients can be categorized into two periods: the pre-LC era and the LC era. The cutoff point is 1987.17 In this article, we extensively review the relevant studies. We focus on surgical indications, procedures, outcomes, and special perspectives related to cholecystectomy in cirrhotic patients. The relevant primary studies after 2000 are summarized in Table 1.
Table 1 . Summary of Relevant Studies Regarding Cholecystectomy for Cirrhotic Patients after 2000.
Author (year) | Study design | Patient numbers (case vs control)* | Morbidity/mortality, % (case vs control) | Conclusions | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
A | B | C | Total | A | B | C | Total | ||||
Fernandes | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 38 | 10 | 0 | 48 vs 187 | NA | NA | NA | 10.4/0 vs 2.1/0 | LC is safe for CTP class A and B cirrhosis. | |
Poggio | Retrospective: cirrhosis+LC vs cirrhosis+OC | 22/17 | 4/7 | 0/0 | 26 vs 24 | NA | NA | NA | 4/0 vs 29/0 | LC is safe for patients with CTP class A and B cirrhosis. There are several advantages over OC, including lower morbidity, shorter operative time, briefer hospital stay, and less transfusion. | |
Clark | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 14 | 9 | 2 | 25 vs 1,275 | 50/0 | 55.6/0 | 50/50 | 52/4 | LC in patients with cirrhosis is associated with significant but acceptable morbidity and mortality rates. | |
Leone | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 19 | 5 | 0 | 24 vs 72 | NA | NA | NA | 20.8/0 vs 9.72/0 | LC is safe for patients with compensated cirrhosis and should be the treatment of choice. | |
Yeh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 193 | 33 | 0 | 226 vs 4,030 | NA | NA | NA | 6.6/0.88 vs 5.3/0.01 | LC is a feasible procedure for most CTP class A and B patients with cholecystolithiasis. | |
Tuech | Retrospective: cirrhosis+LC | 22 | 4 | 0 | 26 | NA | NA | NA | 26.9/0 | LC seems to be safe in selected CTP class A and B patients. | |
Cucinotta | Retrospective: cirrhosis+LC | 12 | 10 | 0 | 22 | NA | NA | NA | 36/0 | LC can be performed safely in selected patients with CTP class A and B cirrhosis. | |
Currò | Retrospective: cirrhosis+LC | 22 | 16 | 4 | 42 | 18/0 | 37.5/0 | 75/50 | 31.0/4.76 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients, but it is a very high-risk procedure in CTP class C patients. | |
Schiff | Retrospective: cirrhosis+LC | NA | NA | 3 | 31 (high risk: 18; intermediate risk: 5; low risk: 8)† | NA | NA | NA | NA | The preoperative degree of coagulopathy instead of the CTP classification predicts the difficulty of LC. | |
da Silveira (2006)44 | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 22 | 11 | 0 | 33 vs 66 | NA | NA | NA | 15.1/0 vs 1.5/0 | LC is a safe and effective alternative to OC in CTP class A and B cirrhotic patients undergoing elective or emergent cholecystectomy. | |
Curro | Retrospective: cirrhosis+LC | 32 | 18 | 0 | 50 | 16/0 | 38/0 | NA | 24/0 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients. | |
Leandros | Retrospective: cirrhosis+LC | 23 | 11 | 0 | 34 | NA | NA | NA | 14.7/2.94 | LC can be carried out in selected patients with well-compensated CTP class A and B liver cirrhosis. | |
Mancero | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 23 | 7 | 0 | 30 vs 60 | 21.6/0 | 57.1/0 | NA | 29.9/0 vs 5/0 | LC may be safely performed in cirrhotic patients. | |
Pavlidis | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 29 | 9 | 0 | 38 vs 1,440 | NA | NA | NA | 7.89/0 vs 1.59/0.13 | LC can be safely performed in CTP class A and B cirrhotic patients with symptomatic gallstone disease. | |
Shaikh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 12 | 8 | 0 | 20 vs 230 | NA | NA | NA | 15.0/0 vs 19.1/0 | LC is an effective and safe treatment for symptomatic gallstone disease in select patients with CTP class A and B cirrhosis. | |
El-Awadi | Prospective: cirrhosis+LC vs cirrhosis+OC | 47/43 | 8/12 | 0/0 | 55 vs 55 | NA | NA | NA | 12.7/0 vs 34.5/0 | Compared with OC, LC offers lower morbidity, a shorter operative time; early resumption of diet with less need for blood transfusion and a reduced hospital stay. | |
Hamad | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 10/10 | 5/5 | 0/0 | 15 vs 15 | NA | NA | NA | 33.4/0 vs 33.4/0 | For CTP class A and B cirrhosis, LC is comparable to OC regarding operative time, morbidity, mortality, and effect on liver function, but with a shorter hospital stay. LC would be the first choice in cirrhotic patients. | |
Lledó | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 26 | 15 | 2 | 43 vs 460 | NA | NA | NA | 37.2/0 vs 6.00/0 | LC is an effective and safe procedure and should be the treatment of choice for symptomatic cholelithiasis or cholecystitis in patients with compensated cirrhosis. | |
Nguyen | Retrospective: cirrhosis+LC | 47 | 19 | 2 | 68 | NA | NA | NA | <7.4/0 | LC in patients with cirrhosis is feasible, with no mortality and low morbidity, especially in patients with CTP class A cirrhosis. |
LC, laparoscopic cholecystectomy; CTP, Child-Turcotte-Pugh; OC, open cholecystectomy; NA, not available..
*The case group comprised cirrhotic patients with intended LC in each study, and the patients were categorized based on the CTP classification; †Risk stratification is defined on the basis of the coagulation function..
For patients with symptomatic cholelithiasis, several interventional procedures, including LC with or without bile duct exploration and endoscopic retrograde cholangiography and pancreatography (ERCP), can be conducted as either single or combined procedures. Since the
For cirrhotic patients with symptoms, the surgical indications of cholecystectomy, especially in the era of LC, have been generally adopted as being similar to those for the general population, except for patients with Child-Turcotte-Pugh (CTP) class C (see the following section).22 In addition, early cholecystectomy should be considered after patients are stabilized because later onset episodes of complications may impose a higher risk on these patients.23,24 Although LC is recognized as a safe procedure under emergency circumstances, even for cirrhotic patients,25 planned and elective LC should be the first choice for symptomatic GB stones.
In the era before LC, OC was the mainstream treatment for symptomatic GB stones, and the outcomes were catastrophic.26,27 In the era of LC, cholecystectomy has become a feasible procedure for cirrhotic patients.28,29 For decades, cirrhotic patients have been recognized as having high surgical risk.29-31 Therefore, preoperative risk stratification for cirrhotic patients is crucial to minimize postoperative complications. Several laboratory parameters32 and scoring systems, including the CTP score and the Model for End-Stage Liver Disease (MELD), have been proposed as risk stratification measures for cirrhotic patients.33-36 The CTP score is the most prevalent tool for preoperative risk stratification. In patients with CTP class C, cholecystectomy is not recommended, and conservative treatment is suggested. Although catastrophic outcomes of OC for CTP class C patients were reported in the 1980s, there have been no case series reporting more than five CTP class C patients undergoing LC-intended procedures. Currò
For CTP classes A and B, LC can be conducted once the surgical indication is justified and meticulous postoperative care is feasible, and most published studies have proven this fact.37,40-50 Nguyen
The MELD score was proposed early in this century and was initially used to predict early death following elective transjugular intrahepatic portosystemic shunts and to help determine organ allocation priorities.51,52 The MELD score is a mathematical model that provides a more accurate prediction power than the CTP does.36 The cutoff value has not yet been established. While a previous retrospective study suggested a MELD score of 13 as a cutoff,36 real-world data published recently by Dolejs
Some laboratory markers, including bilirubin, creatinine, international normalized ratio, and the platelet count, have been proposed as surrogates for preoperative risk stratification.32,33 However, all these factors reflect the severity of hepatic function impairment. In summary, for cirrhotic patients with planned cholecystectomy, precise evaluation of hepatic function is the most important preoperative evaluation in addition to other general preparations. Decompensated liver cirrhosis is the major contraindication for planned cholecystectomy. Surgical treatment for patients with decompensated liver cirrhosis is reserved for life-threatening conditions.
Cholecystectomy has been considered a daunting procedure and can only be performed on cirrhotic patients under “really necessary” conditions.26 In 1985, Bloch
The surgical outcome and safety of LC have been extensively studied compared to the corresponding measures in the general population. Several studies have compared cirrhotic patients with noncirrhotic patients after LC.40,41,44,47,48,62-65 While most of those studies were retrospective, Clark
For cirrhotic patients, liver transplantation is always an option of treatment. Any abdominal surgery, especially hepatobiliary surgery, performed before transplantation may induce peritoneal adhesions, which in turn may increase the difficulty of future transplantation surgery. Polymeneas
The original idea of subtotal cholecystectomy can be traced back to the 19th century.67 In the 1950s, Madding68 suggested that subtotal cholecystectomy could be an alternative to conventional “total cholecystectomy” under circumstances of a difficult cholecystectomy and may be superior to complete cholecystectomy (constrainedly) and cholecystostomy.69 For difficult gallbladders, subtotal cholecystectomy performed by laparoscopy also yields better immediate outcomes with less bile leakage, as reported in a systematic review by Elshaer
Similar to previous studies before the 21st century, Tokyo Guidelines 2018 (TG18), which is based on two systematic reviews, has suggested that subtotal cholecystectomy be considered for difficult situations as a bail-out procedure to avoid serious damage to the bile duct or blood vessels.70-72 Regarding the timing of the publication of TG18, several relevant series related to subtotal cholecystectomy have also been published.73-75 While subtotal cholecystectomy has been recognized as a safe and alternative procedure for total cholecystectomy, the long-term outcome of patients is associated with the presence of retained stones in gallbladder remnants. The rate of retained stones varies from 4% to 15%.70,74 Although most retained stones can be retrieved by ERCP,73 some patients still have to undergo reoperations.75 In general, the rate of long-term complications after subtotal cholecystectomy is higher than that after total cholecystectomy. However, for patients who can “only” undergo subtotal cholecystectomy because of the local condition of the hepatocystic triangle, laparoscopic surgery provides better outcomes than open approach.70
For cirrhotic patients, portal hypertension-associated variceal vessels and a bleeding tendency interfere with the performance of surgery. If good exposure of the hepatocystic triangle cannot be achieved, subtotal cholecystectomy under laparoscopy would be an alternative choice that might prevent patients from experiencing iatrogenic biliary injury, although possible long-term complications should be considered.
Portal hypertension-associated regional anatomic change, variceal vessels, and bleeding tendency may make cholecystectomy even more difficult. Several adjuncts have been applied in various fields of surgery. Several studies related to the application of harmonic scalpels in LC for cirrhotic patients have been published. While some studies revealed that harmonic scalpels may provide benefits with shorter operation times, less blood loss, and even fewer intraoperative GB ruptures,76,77 there was still one investigation that reported no significant benefit from harmonic scalpel use.78 Since all these studies were small in scale, these results might not be convincing. In addition, major complications after LC in the general population are low and acceptable in selected cirrhotic patients. To determine the significant difference under this circumstance, a study with an appropriate sample size would be necessary. In addition, the technique of using energy devices between different surgeons is variable, and this fact cannot be estimated in the aforementioned studies. Further investigation is necessary for this issue. In addition to energy devices, the application of other hemostatic adjuncts, such as oxidized regenerated cellulose and Floseal® (Baxter International, Inc., Deerfield, IL, USA) hemostatic matrix, has also been proposed in LC with positive impact.79,80
Although most of the current evidence recommends LC as a treatment for symptomatic cholelithiasis in cirrhotic patients without decompensation, we can see several pitfalls in all of the relevant studies listed in Table 1: (1) the majority of studies were retrospective; (2) most of the studies enrolled patients with CTP classes A and B; (3) most of the studies presented pooled results instead of subgroup analysis; and (4) the definitions of complications varied from study to study. While de Goede
Based on currently available evidence, we propose a flow chart for the management of cirrhotic patients with GB stones (Fig. 2).81,82 The prevalence of cholelithiasis is relatively high in cirrhotic patients, and the surgical indications for LC in these patients are the same as those for noncirrhotic patients. Once the surgical indication is justified, meticulous preoperative evaluation is crucial. Advanced cirrhosis, such as CTP class C, is the contraindication for surgery. LC is the procedure of choice, just as for the general population. Postoperative management is also particularly important due to the relatively high, although acceptable, rate of complications.
We would like to thank the Chang Gung Memorial Hospital for supporting our research (CMRPG3D0281).
No potential conflict of interest relevant to this article was reported.
Table 1 Summary of Relevant Studies Regarding Cholecystectomy for Cirrhotic Patients after 2000
Author (year) | Study design | Patient numbers (case vs control)* | Morbidity/mortality, % (case vs control) | Conclusions | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
A | B | C | Total | A | B | C | Total | ||||
Fernandes | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 38 | 10 | 0 | 48 vs 187 | NA | NA | NA | 10.4/0 vs 2.1/0 | LC is safe for CTP class A and B cirrhosis. | |
Poggio | Retrospective: cirrhosis+LC vs cirrhosis+OC | 22/17 | 4/7 | 0/0 | 26 vs 24 | NA | NA | NA | 4/0 vs 29/0 | LC is safe for patients with CTP class A and B cirrhosis. There are several advantages over OC, including lower morbidity, shorter operative time, briefer hospital stay, and less transfusion. | |
Clark | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 14 | 9 | 2 | 25 vs 1,275 | 50/0 | 55.6/0 | 50/50 | 52/4 | LC in patients with cirrhosis is associated with significant but acceptable morbidity and mortality rates. | |
Leone | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 19 | 5 | 0 | 24 vs 72 | NA | NA | NA | 20.8/0 vs 9.72/0 | LC is safe for patients with compensated cirrhosis and should be the treatment of choice. | |
Yeh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 193 | 33 | 0 | 226 vs 4,030 | NA | NA | NA | 6.6/0.88 vs 5.3/0.01 | LC is a feasible procedure for most CTP class A and B patients with cholecystolithiasis. | |
Tuech | Retrospective: cirrhosis+LC | 22 | 4 | 0 | 26 | NA | NA | NA | 26.9/0 | LC seems to be safe in selected CTP class A and B patients. | |
Cucinotta | Retrospective: cirrhosis+LC | 12 | 10 | 0 | 22 | NA | NA | NA | 36/0 | LC can be performed safely in selected patients with CTP class A and B cirrhosis. | |
Currò | Retrospective: cirrhosis+LC | 22 | 16 | 4 | 42 | 18/0 | 37.5/0 | 75/50 | 31.0/4.76 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients, but it is a very high-risk procedure in CTP class C patients. | |
Schiff | Retrospective: cirrhosis+LC | NA | NA | 3 | 31 (high risk: 18; intermediate risk: 5; low risk: 8)† | NA | NA | NA | NA | The preoperative degree of coagulopathy instead of the CTP classification predicts the difficulty of LC. | |
da Silveira (2006)44 | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 22 | 11 | 0 | 33 vs 66 | NA | NA | NA | 15.1/0 vs 1.5/0 | LC is a safe and effective alternative to OC in CTP class A and B cirrhotic patients undergoing elective or emergent cholecystectomy. | |
Curro | Retrospective: cirrhosis+LC | 32 | 18 | 0 | 50 | 16/0 | 38/0 | NA | 24/0 | LC is a safe procedure in well-selected CTP class A and B cirrhotic patients. | |
Leandros | Retrospective: cirrhosis+LC | 23 | 11 | 0 | 34 | NA | NA | NA | 14.7/2.94 | LC can be carried out in selected patients with well-compensated CTP class A and B liver cirrhosis. | |
Mancero | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 23 | 7 | 0 | 30 vs 60 | 21.6/0 | 57.1/0 | NA | 29.9/0 vs 5/0 | LC may be safely performed in cirrhotic patients. | |
Pavlidis | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 29 | 9 | 0 | 38 vs 1,440 | NA | NA | NA | 7.89/0 vs 1.59/0.13 | LC can be safely performed in CTP class A and B cirrhotic patients with symptomatic gallstone disease. | |
Shaikh | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 12 | 8 | 0 | 20 vs 230 | NA | NA | NA | 15.0/0 vs 19.1/0 | LC is an effective and safe treatment for symptomatic gallstone disease in select patients with CTP class A and B cirrhosis. | |
El-Awadi | Prospective: cirrhosis+LC vs cirrhosis+OC | 47/43 | 8/12 | 0/0 | 55 vs 55 | NA | NA | NA | 12.7/0 vs 34.5/0 | Compared with OC, LC offers lower morbidity, a shorter operative time; early resumption of diet with less need for blood transfusion and a reduced hospital stay. | |
Hamad | Prospective: cirrhosis+LC vs non-cirrhosis+LC | 10/10 | 5/5 | 0/0 | 15 vs 15 | NA | NA | NA | 33.4/0 vs 33.4/0 | For CTP class A and B cirrhosis, LC is comparable to OC regarding operative time, morbidity, mortality, and effect on liver function, but with a shorter hospital stay. LC would be the first choice in cirrhotic patients. | |
Lledó | Retrospective: cirrhosis+LC vs non-cirrhosis+LC | 26 | 15 | 2 | 43 vs 460 | NA | NA | NA | 37.2/0 vs 6.00/0 | LC is an effective and safe procedure and should be the treatment of choice for symptomatic cholelithiasis or cholecystitis in patients with compensated cirrhosis. | |
Nguyen | Retrospective: cirrhosis+LC | 47 | 19 | 2 | 68 | NA | NA | NA | <7.4/0 | LC in patients with cirrhosis is feasible, with no mortality and low morbidity, especially in patients with CTP class A cirrhosis. |
LC, laparoscopic cholecystectomy; CTP, Child-Turcotte-Pugh; OC, open cholecystectomy; NA, not available.
*The case group comprised cirrhotic patients with intended LC in each study, and the patients were categorized based on the CTP classification; †Risk stratification is defined on the basis of the coagulation function.