
==== Front
Ann Surg Open
Ann Surg Open
AS9
Annals of Surgery Open
2691-3593
Wolters Kluwer Health, Inc. Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103

AOSO-D-24-00103
00002
10.1097/AS9.0000000000000454
3
Meta-Analysis
Short-term Outcomes of Pancreatoduodenectomy in Patients with Liver Cirrhosis: A Systematic Review and Meta-analysis
Hajibandeh Shahab MRCS *
Hajibandeh Shahin FRCS †
Puthiyakunnel Saji Alwin ‡
Ashabi Ayman MRCS *
Brown Christopher FRCS *
Mowbray Nicholas G FRCS *
Mortimer Matthew FRCS *
Shingler Guy FRCS *
Kambal Amir FRCS *
Al-Sarireh Bilal FRCS, PhD *
From the * Department of Hepatobiliary and Pancreatic Surgery, Morriston Hospital, Swansea, UK
† Department of Hepatobiliary and Pancreatic Surgery, Royal Stoke University Hospital, Stoke-on-Trent, UK
‡ School of Medicine, Cardiff University, Cardiff, UK
Reprints: Alwin Puthiyakunnel Saji, School of Medicine, Cardiff University, Cardiff, UK. E-mail: puthiyakunnelsajia@cardiff.ac.uk.
25 6 2024
9 2024
5 3 e454e454
23 4 2024
27 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Objectives:

The objective of this study was to compare short-term outcomes of pancreatoduodenectomy between patients with and without liver cirrhosis (LC).

Background:

It is not uncommon to encounter a patient with LC and with an indication for pancreatoduodenectomy; however, the knowledge on the outcomes after pancreatoduodenectomy in patients with LC is poorly developed.

Methods:

A systematic review and meta-analysis was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards. Short-term outcomes of pancreatoduodenectomy between patients with and without LC were compared using random effects modeling and the certainty of the evidence was assessed using the GRADE system.

Results:

Analysis of 18,184 patients from 11 studies suggested LC increased the risk of postoperative mortality (odds ratio [OR]: 3.94, P < 0.00001), major complications (OR: 2.25, P = 0.0002), and pancreatic fistula (OR: 1.73, P = 0.03); it resulted in more blood loss (mean difference [MD]: 204.74 ml, P = 0.0003) and longer hospital stay (MD: 2.05 days, P < 0.00001). LC did not affect delayed gastric emptying (OR: 1.33, P = 0.21), postoperative bleeding (OR: 1.28, P = 0.42), and operative time (MD: 3.47 minutes, P = 0.51). Among the patients with LC, Child-Pugh B or C class increased blood loss (MD: 293.33 ml, P < 0.00001), and portal hypertension increased postoperative mortality (OR: 2.41, P = 0.01); the other outcomes were not affected.

Conclusions:

Robust evidence with high certainty suggests LC of any severity with or without portal hypertension results in at least a fourfold increase in mortality and a twofold increase in morbidity after pancreatoduodenectomy. Whether such risks increase with the severity of the liver disease or decrease with optimization of underlying liver disease should be the focus of future research.

liver cirrhosis
morbidity
mortality
pancreatoduodenectomy
OPEN-ACCESSTRUE
SDCT
==== Body
pmcINTRODUCTION

Pancreatoduodenectomy (PD) is recognized as a technically complex operation with a conspicuous risk of morbidity; hence, there is an ongoing effort to predict and reduce the risk of morbidity after PD.1–3 PD remains the only curative treatment for pancreatic and periampullary cancers which occur more frequently in patients with liver cirrhosis than those without cirrhosis.4,5 Consequently, it is not uncommon to encounter a patient with liver cirrhosis and with an indication for PD. This means a high-risk operation in a high-risk patient as liver cirrhosis is a recognized risk factor for postoperative complications; the more severe the liver cirrhosis, the higher the risk of early postoperative morbidity and mortality.6,7

The knowledge base regarding postoperative morbidity and mortality outcomes after PD in patients with liver cirrhosis is poorly developed. Such knowledge is valuable to multidisciplinary teams when formulating the management plan for a patient with liver cirrhosis who requires PD. The outcomes of PD in patients with liver cirrhosis have been evaluated by several observational studies providing a robust rationale for conducting a comparative meta-analysis. Considering that cirrhosis is a prognostic factor rather than an intervention, performing a randomized controlled trial is not possible in this setting as cirrhosis cannot be randomized; hence, a meta-analysis of observational studies serves as the best evidence. In view of the above, we aimed to conduct a systematic review and meta-analysis to compare short-term outcomes of PD between patients with liver cirrhosis and those without cirrhosis.

METHODS

This study was protocoled (PROSPERO registration number: CRD42024531188), conducted, and reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards.8

Eligibility Criteria

Study Design

All prospective and retrospective comparative observational studies were considered for inclusion. As explained previously, a randomized controlled trial is not feasible in this setting because cirrhosis cannot be randomized.

Population

All patients aged 18 years or older who underwent open or minimally invasive PD due to either benign or malignant indications were considered eligible for inclusion.

Prognostic Factor of Interest and Comparison

Liver cirrhosis of any severity was considered as the prognostic factor of interest, and no liver cirrhosis was considered as the comparison.

Outcomes

Postoperative mortality and major complications (Clavien–Dindo ≥3) were considered as primary outcomes. The secondary outcomes included intraoperative blood loss, operative time, grade B-C postoperative pancreatic fistula, postoperative bleeding, delayed gastric emptying, and length of hospital stay.

Search Methods

A comprehensive search strategy was created by 2 independent authors with experience in evidence synthesis using proper search limits, keywords, thesaurus headings, and operators (Appendix I, http://links.lww.com/AOSO/A363). The search strategy had no language restrictions and was last run on March 20, 2024. The reference lists of relevant systematic reviews and original studies were also evaluated to find more eligible studies.

Study Selection and Data Extraction

The title and abstract of the identified articles were screened, and the full texts of relevant articles were retrieved by 2 independent authors who included the studies that met the eligibility criteria. An electronic data collection proforma was evaluated based on randomly selected studies and included information on the name of the first author, year of publication, name of journal, type of study design, description of the included population, sample size of each study, age, gender, Child-Pugh class, model for end-stage liver disease (MELD) score, portal hypertension, and the already mentioned outcomes. The 2 independent authors discussed and resolved disagreements during study data extraction, and a third independent author was consulted if required.

Risk of Bias Assessment

Two independent authors evaluated the methodological quality of the included studies using the Quality In Prognosis Studies tool, which evaluates the risk of bias in studies of prognostic factors in terms of study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting.9

Data Analysis

Review Manager 5.4 software was used for meta-analysis. The odds ratio (OR) and mean difference (MD) were calculated as summary measures for dichotomous and continuous outcomes, respectively. The random effects modeling was used for analyses and forest plots with 95% confidence intervals (CIs) were constructed to present the results. Individual patients were considered as the unit of analysis. Meta-regression analysis was modeled to evaluate the effect of differences in Child-Pugh class, MELD score, and portal hypertension in cirrhotic patients among the included studies on the primary outcomes. The statistical heterogeneity was measured as I2 using the Cochran Q test (χ2) and it was classified as low heterogeneity when I2 was 0–25%, moderate heterogeneity when I2 was 25–75%, and high heterogeneity when I2 was 75–100%. The risk of publication bias was evaluated by constructing funnel plots for outcomes reported by at least 10 studies.

Additional Analyses

The following comparisons were made among the patients with liver cirrhosis: (1) patients with Child-Pugh B or C disease versus patients with Child-Pugh A and (2) patients with portal hypertension versus patients without portal hypertension.

Sensitivity Analyses

To evaluate the consistency and robustness of the results, a sensitivity analysis was performed for the outcomes reported by a minimum number of 4 studies: (1) leave-one-out analysis to investigate the effect of each study on the pooled outcomes; (2) Separate analysis of studies with low overall risk of bias.

Certainty of Evidence

Certainty of evidence was judged based on the recommended standards and domains by the GRADE system.10

RESULTS

Literature Search Results

The search of electronic databases produced 278 articles, of which 266 articles were excluded directly because they were not relevant to the subject of this study. After reviewing the full text of the remaining 12 articles, 1 more article was excluded because it was a review article. Consequently, 11 comparative studies11–21 including a total of 18,184 patients were included. Among the included population, 1001 patients had liver cirrhosis and 17,183 patients did not have liver cirrhosis. The study flow chart is shown in Figure 1. The baseline characteristics of the included studies and included populations are shown in Tables 1 and 2, respectively.

TABLE 1. Baseline Characteristics of the Included Studies

Study	Country	Journal	Design	Population	Sample Size	
Total	No Cirrhosis	Cirrhosis	
Nevarez et al (2023)11	USA	HPB	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	16,355	16,152	203	
Zamorano et al 202312	USA	Langenbecks Arch Surg	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	48	32	16	
Kang et al 202313	South Korea	Acta Chir Belg	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	221	196	25	
Cheng et al 202114	China	PLoS One	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	84	56	28	
Enderes et al 202115	Germany	J Clin Med	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	255	240	15	
Futagawa et al 201916	Japan	J Hepatobiliary Pancreat Sci	Retrospective observational	Patients with cirrhosis undergoing elective pancreatoduodenectomy	529	0	529	
Butler et al 201817	USA	HPB	Retrospective observational	Patients with cirrhosis undergoing elective pancreatoduodenectomy	36	0	36	
Busquets et al 201618	Spain	Cir Esp	Prospective observational	Patients undergoing elective pancreatoduodenectomy	45	30	15	
Regimbeau et al 201519	France	J Surg Oncol	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	105	70	35	
Nakeeb et al 201320	Egypt	World J Gastroenterol	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	442	375	67	
Warnick et al 201121	Germany	Pancreatology	Retrospective observational	Patients undergoing elective pancreatoduodenectomy	64	32	32	

TABLE 2. Baseline Characteristics of the Included Population

Study	Age* Mean (SD)	Female* No/Total (%)	Child–Pugh Class in Cirrhotic Patients
No/Total (%)	MELD Score in Cirrhotic Patients mean (SD)	Portal Hypertension*
No/Total (%)	
A	B	C	
Nevarez et al 202311	65 (23) vs 65 (21)	7757/16152 (48%) vs 80/203 (39%)	NR	NR	NR	NR	37/16152 (0.2%) vs 16/203 (8%)	
Zamorano et al 202312	68 (12) vs 63 (10)	18/32 (56%) vs 8/16 (50%)	NR	NR	NR	NR	0/32 (0%) vs 2/16 (13%)	
Kang et al 202313	64 (12) vs 63 (10)	90/196 (45%) vs 12/25 (48%)	NR	NR	NR	8 (2.3)	0/196 (0%) vs 13/25 (52%)	
Cheng et al 202114	60 (5) vs 62 (5)	14/56 (25%) vs 7/28 (25%)	11/28 (39%)	17/28 (61%)	0/28 (0%)	12 (2.3)	NR	
Enderes et al 202115	68 (4) vs 63 (5)	106/204 (51%) vs 5/15 (33%)	13/15 (87%)	3/15 (13%)	0/15 (0%)	NR	NR	
Futagawa et al 201916	70 (3)	105/529 (19%)	427/529 (81%)	98/529 (18%)	4/529 (1%)	NR	63/529 (12%)	
Butler et al 201817	60 (13)	20/36 (55%)	30/36 (83%)	6/36 (17%)	0/36 (0%)	9	16/29 (55%)	
Busquets et al 201618	62 (11) vs 64 (9)	7/30 (23%) vs 4/15 (26%)	15/15 (100%)	0/15 (0%)	0/15 (0%)	NR	NR	
Regimbeau et al 201519	59 (11) vs 59 (10)	18/70 (25%) vs 7/35 (20%)	35/35 (100%)	0/35 (0%)	0/35 (0%)	10 (8)	0/70 (0%) vs 6/35 (17%)	
Nakeeb et al 201320	53 (11) vs 54 (9)	150/375 (40%) vs 15/67 (22%)	63/67 (94%)	4/67 (6%)	0/67 (0%)	NR	0/375 (0%) vs 16/67 (24%)	
Warnick et al 201121	57 (12) vs 57 (12)	7/32 (21%) vs 7/32 (21%)	30/32 (94%)	2/32 (6%)	0/32 (0%)	11 (5)	NR	
* No cirrhosis group versus cirrhosis group.

MELD indicates model for end-stage liver disease; NR: not reported; SD, standard deviation.

FIGURE 1. Study PRISMA flow diagram

Risk of Bias Assessment

Supplementary Figure 1, http://links.lww.com/AOSO/A363 highlights the outcomes of methodological quality assessment based on the Quality In Prognosis Studies tool. All the included studies were judged to be of low risk of bias in terms of study participation, study attrition, outcome measurement, and statistical analysis and reporting. The risk of bias due to prognostic factor measurement was judged to be low in 10 studies and unclear in 1 study. The risk of bias due to study confounding was judged to be low in 6 studies and unclear in 5 studies.

Primary Outcomes

Postoperative Mortality

Analysis of 17,619 patients from 9 studies showed that the risk of postoperative mortality was higher in patients with liver cirrhosis (OR: 3.94, 95% CI = 2.73–5.69, P < 0.00001) (Fig. 2A). The statistical between-study heterogeneity was low (I2 = 0%, P = 0.75) and the GRADE certainty of the evidence was high (Supplementary Table 1, http://links.lww.com/AOSO/A363). Meta-regression showed that the risk of postoperative mortality was not influenced by the differences in Child-Pugh class (coefficient: 0.01, P = 0.685), MELD score (coefficient: 0.037, P = 0.933) and portal hypertension (coefficient: 0.014, P = 0.536) in cirrhotic patients among the included studies (Table 3 and Supplementary Figure 2, http://links.lww.com/AOSO/A363).

TABLE 3. Results of Meta-regression Analyses for the Primary Outcomes

	Postoperative Mortality	Major Complications (Clavien-Dindo ≥3)	
Coefficient	P value	Coefficient	P value	
Child–Pugh class*	0.01	0.685	0.017	0.195	
MELD score	0.037	0.933	0.016	0.927	
Portal hypertension	0.014	0.536	-0.005	0.73	
* Percentage of Child-Pugh A in each study was used for analyses.

MELD indicates model for end-stage liver disease.

FIGURE 2. Forest plots for comparison between liver cirrhosis and no liver cirrhosis: (A) postoperative mortality. (B) Major complications (Clavien-Dindo ≥3). (C) Intraoperative blood loss. (D) Operative time. (E) Grade B-C postoperative pancreatic fistula. (F) postoperative bleeding. (G) Delayed gastric emptying. (H) Length of hospital stay.

Major Complications (Clavien-Dindo ≥3)

Analysis of 777 patients from 6 studies showed that the risk of major complications (Clavien-Dindo ≥3) was higher in patients with liver cirrhosis (OR: 2.25, 95% CI = 1.48–3.43, P = 0.0002) (Fig. 2B). The statistical between-study heterogeneity was low (I2 = 0%, P = 0.50) and the GRADE certainty of the evidence was high (Supplementary Table 1, http://links.lww.com/AOSO/A363). Meta-regression showed that the risk of major complications was not influenced by the differences in Child-Pugh class (coefficient: 0.017, P = 0.195), MELD score (coefficient: 0.016, P = 0.927), and portal hypertension (coefficient: −0.005, P = 0.730) in cirrhotic patients among the included studies (Table 3 and Supplementary Figure 2, http://links.lww.com/AOSO/A363).

Secondary Outcomes

Intraoperative Blood Loss

Analysis of 1107 patients from 5 studies showed that liver cirrhosis resulted in more intraoperative blood loss (MD: 204.74 ml, 95% CI = 92.76–316.72, P = 0.0003) (Fig. 2C). The statistical between-study heterogeneity was high (I2 = 92%, P < 0.00001) and the GRADE certainty of the evidence was moderate (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Operative Time

Analysis of 1354 patients from 7 studies showed no difference in operative time between patients with and without liver cirrhosis (MD: 3.47 minutes, 95% CI = −6.74 to 13.68, P = 0.51) (Fig. 2D). The statistical between-study heterogeneity was moderate (I2 = 40%, P = 0.12) and the GRADE certainty of the evidence was moderate (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Grade B-C Postoperative Pancreatic Fistula

Analysis of 1114 patients from 6 studies showed that the risk of grade B-C postoperative pancreatic fistula was higher in patients with liver cirrhosis (OR: 1.73, 95% CI = 1.05–2.84, P = 0.39) (Fig. 2E). The statistical between-study heterogeneity was low (I2 = 4%, P = 0.50) and the GRADE certainty of the evidence was moderate (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Postoperative Bleeding

Analysis of 1043 patients from 7 studies showed that liver cirrhosis did not affect the risk of postoperative bleeding (OR: 1.28, 95% CI = 0.70–2.36, P = 0.42) (Fig. 2F). The statistical between-study heterogeneity was low (I2 = 0%, P = 0.73) and the GRADE certainty of the evidence was high (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Delayed Gastric Emptying

Analysis of 980 patients from 6 studies showed that liver cirrhosis did not affect the risk of delayed gastric emptying (OR: 1.33, 95% CI = 0.86–2.07, P = 0.21) (Fig. 2G). The statistical between-study heterogeneity was low (I2 = 0%, P = 0.73) and the GRADE certainty of the evidence was high (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Length of Hospital Stay

Analysis of 1112 patients from 6 studies showed that liver cirrhosis resulted in longer length of hospital stay (MD: 2.05 days, 95% CI = 1.40–2.69, P < 0.00001) (Fig. 2H). The statistical between-study heterogeneity was low (I2 = 0%, P = 0.70) and the GRADE certainty of the evidence was high (Supplementary Table 1, http://links.lww.com/AOSO/A363).

Child-Pugh B or C Disease Versus Child-Pugh A in Cirrhotic Patients

Child-Pugh B or C class was associated with more intraoperative blood loss compared with Child-Pugh A class (MD: 293.33 ml, 95% CI = 231.96–354.71, P < 0.00001). There was no difference between Child-Pugh B or C class and Child-Pugh A class in postoperative mortality (OR: 2.56, 95% CI = 0.55–11.81, P = 0.23), major complications (Clavien-Dindo ≥3) (OR: 2.71, 95% CI = 0.32–23.13, P = 0.36), operative time (MD: 121.18 minutes, 95% CI = −68.84 to 311.20, P = 0.21), grade B-C postoperative pancreatic fistula (OR: 1.33, 95% CI = 0.24–7.35, P = 0.74), postoperative bleeding (OR: 2.64, 95% CI = 0.45–15.66, P = 0.28), delayed gastric emptying (OR: 0.72, 95% CI = 0.32–1.58, P = 0.41), and length of hospital stay (MD: 2.03 days, 95% CI = 0.01–4.05, P = 0.05) (Table 4 and Supplementary Figure 3, http://links.lww.com/AOSO/A363).

TABLE 4. Comparison of the Outcomes in Cirrhotic Patients Based on Child–Pugh Class and Portal Hypertension Status

		Number of Studies	Number of Patients	Summary Measure OR (95% CI)	P-value	Heterogeneity, I2	
Child-Pugh B or C
vs
Child–Pugh A	Postoperative mortality	3	600	OR: 2.56 (0.55–11.81)	0.23	55%	
Major complications (Clavien-Dindo ≥3)	3	99	OR: 2.71 (0.32–23.13)	0.36	67%	
Intraoperative blood loss	2	565	MD: 293.33 ml (231.96–354.71)	<0.00001	0%	
Operative time	2	565	MD: 121.18 minutes (−68.84 to 311.20)	0.21	89%	
Grade B-C postoperative pancreatic fistula	1	26	OR: 1.33 (0.24–7.35)	0.74	NA	
Postoperative bleeding	3	600	OR: 2.64 (0.45–15.66)	0.28	44%	
Delayed gastric emptying	3	592	OR: 0.72 (0.32–1.58)	0.41	0%	
Length of hospital stay	2	565	MD: 2.03 days (0.01–4.05)	0.05	0%	
Portal hypertension
vs
No portal hypertension	Postoperative mortality	4	630	OR: 2.41 (1.20–4.86)	0.01	0%	
Major complications (Clavien-Dindo ≥3)	2	54	OR: 1.49 (0.50–4.47)	0.47	0%	
Intraoperative blood loss	2	54	MD: 196.56 ml (−104.20 to 497.33)	0.20	0%	
Operative time	3	121	MD: 23.06 minutes (−10.70, 56.82)	0.18	58%	
Grade B-C postoperative pancreatic fistula	2	92	OR: 2.57 (0.86–7.71)	0.09	0%	
Postoperative bleeding	2	96	OR: 3.90 (0.87–17.50)	0.08	0%	
Delayed gastric emptying	1	67	OR: 2.50 (0.61–10.31)	0.20	NA	
Length of hospital stay	2	96	MD: 1.35 days (−6.38 to 9.09)	0.73	50%	
CI indicates confidence interval; MD, mean difference; OR, odds ratio.

Portal Hypertension Versus No Portal Hypertension in Cirrhotic Patients

Portal hypertension was associated with a higher risk of postoperative mortality (OR: 2.41, 95% CI = 1.20–4.86, P = 0.01) and longer length of hospital stay (MD: 1.35 days, 95% CI = −6.38 to 9.09, P = 0.73) compared with no portal hypertension. There was no difference between cirrhotic patients with or without portal hypertension in major complications (Clavien-Dindo ≥ 3) (OR: 1.49, 95% CI = 0.50–4.47, P = 0.36), intraoperative blood loss (MD: 196.56 ml, 95% CI = −104.20 to 497.33, P = 0.20), operative time (MD: 23.06 minutes, 95% CI −10.70 to 56.82, P = 0.18), grade B-C postoperative pancreatic fistula (OR: 2.57, 95% CI = 0.86–7.71, P = 0.09), postoperative bleeding (OR: 3.90, 95% CI = 0.87–17.50, P = 0.08), and delayed gastric emptying (OR: 2.50, 95% CI = 0.61–10.31, P = 0.20) (Table 4 and Supplementary Figure 4, http://links.lww.com/AOSO/A363).

Sensitivity Analyses

Sensitivity analyses confirmed the consistency of the results for the primary outcomes and most of the secondary outcomes except postoperative pancreatic fistula and operative time. Leave-one-out analysis changes the direction of the effect size toward no difference in postoperative pancreatic fistula and in favor of no cirrhosis in operative time. However, separate analysis of studies with low overall risk of bias did not affect the pooled risk of any of the outcomes.

DISCUSSION

A systematic review and meta-analysis was conducted to compare short-term outcomes of PD between patients with liver cirrhosis and those without cirrhosis. Analysis of 18,184 patients from 11 studies showed that liver cirrhosis increased the risks of postoperative mortality (high certainty), major complications (high certainty), and grade B-C postoperative pancreatic fistula (moderate certainty); it resulted in more intraoperative blood loss (moderate certainty) and longer length of hospital stay (high certainty). Liver cirrhosis did not affect delayed gastric emptying (high certainty), postoperative bleeding (high certainty), and operative time (moderate certainty). Meta-regression analyses suggested that postoperative morbidity and morbidity existed irrespective of Child-Pugh class, MELD score, and portal hypertension. Among the patients with liver cirrhosis, Child-Pugh B or C class increased intraoperative blood loss, and portal hypertension increased the risk of postoperative mortality; however, the other outcomes were not affected.

This study is the first comprehensive comparative meta-analysis in the literature with a reasonable sample size and methodology evaluating the effect of liver cirrhosis on short-term outcomes after PD; however, the risks of complications following pancreatic surgery in cirrhotic patients have been quantified previously by Schizas et al22 who conducted a systematic review of 5 observational studies and 8 reported cases. The study by Schizas et al22 concluded that pancreatic surgery in patients with liver cirrhosis is associated with increased risks of postoperative morbidity and mortality. Although the statistical methods used in the study by Schizas et al22 for comparing the outcomes between patients with and without cirrhosis are subject to bias, their findings support the findings of the current study. Artinyan et al6 retrospectively analyzed 106,729 patients who underwent resection for gastrointestinal malignancy and concluded that liver cirrhosis is associated with poor early postoperative and transitional outcomes. Ng et al23 and Deng et al24 reported similar findings in colorectal surgery and oesophagectomies, respectively. All of the above support the external validity of the findings of the current study.

The results of the current study suggest that liver cirrhosis of any severity with or without portal hypertension increases the risk of morbidity and mortality after PD. While we did not robustly demonstrate the actual relationship between the severity of the liver disease and increased risks of morbidity and mortality, this could be a type 2 error due to the small sample size for separate analyses of cirrhotic patients based on Child-Pugh class and portal hypertension status. This may be reflected by some of the reported P values in Table 4 which are approaching 0.05 value. Nevertheless, others have demonstrated that the more severe the liver cirrhosis, the higher the risk of early postoperative morbidity and mortality.6,7

The findings of the current study may be useful to multidisciplinary teams when formulating management plans for patients with liver cirrhosis and with indications for PD and when discussing the risks of surgery with such patients. Based on the available data, we can confidently with high certainty say that liver cirrhosis results in at least a fourfold increase in postoperative mortality and a twofold increase in postoperative morbidity in patients undergoing PD. Whether such risks increase with the severity of the liver disease or decrease with optimization of undergoing liver disease should be the focus of future research.

The study has inherent limitations. The retrospective nature of the included studies introduces the inevitable risk of selection and confounding bias. As mentioned earlier, considering that cirrhosis is a prognostic factor rather than an intervention, performing a randomized controlled trial is not feasible in this setting as cirrhosis cannot be randomized; hence, a meta-analysis of observational studies serves the best evidence. We could not formally assess the risk of publication bias because none of the outcomes were reported by more than 10 studies; hence, selective reporting cannot be excluded. Sensitivity analyses suggested that our findings regarding postoperative pancreatic fistula and operative time were not robust; nevertheless, we downgraded the certainty of evidence for these outcomes accordingly. Finally, as mentioned earlier our findings regarding the relationship between the severity of the liver disease and increased risks of morbidity and mortality may be subject to type 2 error. In contrast, the study has strengths. An objective and systematic approach was used in evidence synthesis, consistent with the appropriate and required standards. A GRADE system was used to evaluate the certainty of evidence for each outcome, considering the risk of bias, directness of evidence, heterogeneity, precision of effects estimates, and risk of publication bias. The adequate sample size, low between-study heterogeneity, high-GRADE certainty, and appropriate meta-regression analyses would make our conclusions about the primary outcomes robust.

CONCLUSIONS

Robust evidence with high certainty suggests that liver cirrhosis of any severity with or without portal hypertension results in at least a fourfold increase in mortality and a twofold increase in morbidity after pancreatoduodenectomy. Whether such risks increase with the severity of the liver disease or decrease with optimization of underlying liver disease should be the focus of future research.

Supplementary Material

Shahab Hajibandeh, Shahin Hajibandeh, and Alwin Puthiyakunnel Saji are joint first authors.

Disclosure: The authors declare that they have nothing to disclose.

Lead: B.A. Conception and design: B.A., Shahab H. Data collection and data analysis: Shahab H, Shahin H. Analysis and interpretation, writing the article, critical revision of the article, final approval of the article, The data and materials related to this study will be available upon reasonable request from the corresponding author.

This study is a systematic review with meta-analysis of outcomes which does not include research directly involving human or animal participation.

PROSPERO registration number: CRD42024531188.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.annalsofsurgery.com).
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