Chronic liver disease is an important risk factor for worse outcomes in acute pancreatitis: a systematic review and meta-analysis

Chronic liver diseases (CLD) affect 1.5 billion patients worldwide, with dramatically increasing incidence in recent decades. It has been hypothesized that the chronic hyperinflammation associated with CLD may increase the risk of a more severe course of acute pancreatitis (AP). This study aims to investigate the underlying impact of CLD on the outcomes of AP. A systematic search was conducted in Embase, Medline, and Central databases until October 2022. Studies investigating patients with acute pancreatitis and CLD, were included in the meta-analysis. A total of 14,963 articles were screened, of which 36 were eligible to be included. CLD was a risk factor for increased mortality with an odds ratio (OR) of 2.53 (CI 1.30 to 4.93, p = 0.01). Furthermore, renal, cardiac, and respiratory failures were more common in the CLD group, with ORs of 1.92 (CI 1.3 to 2.83, p = 0.01), 2.11 (CI 0.93 to 4.77, p = 0.062) and 1.99 (CI 1.08 to 3.65, p = 0.033), respectively. Moreover, the likelihood of developing Systemic Inflammatory Response Syndrome (SIRS) was significantly higher, with an OR of 1.95 (CI 1.03 to 3.68, p = 0.042). CLD is an important risk factor for worse outcomes in AP pancreatitis, leading to higher mortality and increased rates of local and systemic complications.


Risk of bias assessment
Half of the publications had a low ROB, 31% had a moderate, and 20% had a high ROB.This is the result of the high number of conference abstracts and poor diagnostic criteria for CLD in some studies.For an overview of ROB, see (Fig. 7) and Supplementary (Supplementary Table S1).

Discussion
This systematic review and meta-analysis investigated the impact of CLD on the outcomes among patients with AP.This work provides compelling evidence that CLD significantly increases both the mortality and severity of AP.Furthermore, our analysis showed that both local and systemic complications were higher in the CLD group.
Both CLD and AP are among the most common diseases in gastroenterology.The etiology of AP can be traced to biliary gallstones, which account for 45% of cases; alcohol consumption accounts for 20% of cases, AP caused by hypertriglyceridemia accounts for approximately 5% of cases, and the remaining 30% are due to less common causes 50 .Striking overlaps can be observed in the etiological factors of AP and CLD, such as the association between alcohol consumption and the risk of ALD or cirrhosis and alcohol-induced AP.Similarly, the relationship between the development of biliary gallstones or hypertriglyceridemia in obese patients with NAFDL/MAFLD overlaps with the risk of biliary and hypertriglyceridemia-induced AP in obese patients 51,52 .
This overlap is reflected in multiple studies that have demonstrated a higher incidence of CLD in patients with AP.For example, Simons-Linares et al. conducted a large database-based study of 2.8 million patients with AP in the US, which found a prevalence of cirrhosis of 2.8% (80,093), ten times higher than the prevalence of cirrhosis in the general US population (0.27%) 34,53 .Similarly, the Hungarian Pancreatic Study Group conducted a prospective cohort study and reported a 39% prevalence of MAFLD compared to a 23% prevalence in the general population.Furthermore, hypertriglyceridemia-induced AP was significantly more common in the MAFDL group (14% vs. 3%) 44,54 .
Our meta-analysis observed a tendency for worse outcomes for CLD patients in all measured parameters.The pooled OR for mortality was found to be 2.5 times higher in the CLD group, with statistical significance.Subgroup analysis of mortality showed a higher mortality trend in patients with cirrhosis.However, no definitive conclusion could be drawn due to the small sample size and broad CI.Multiple database-based studies with large sample sizes reported mortality and other outcomes, but these data could not be included in the meta-analysis due to overlapping populations 23,30,33,34 .However, the effect size in these studies was relatively similar to the pooled one, with mortality ORs for each study ranging from 1.8 to 2.4, increasing the validity of the meta-analysis findings.The database-based study with the largest sample by Simons-Linares et al. 34 identified decompensated cirrhosis as the risk factor associated with the highest odds for in-hospital mortality, with an adjusted OR of 1.4 for decompensated vs. compensated cirrhosis and 2.4 for decompensated vs. no cirrhosis.CLD patients with decompensated cirrhosis constitute a specific subgroup with distinct comorbidities associated with liver malfunction.This makes these patients much more vulnerable, especially due to their susceptibility to trigger acute-onchronic liver failure (ACLF), a syndrome characterized by acute decompensation of cirrhosis, organ failure(s), and high short-term mortality.Vogel et al. 35 reported that the incidence of ACLF was 44% in AP patients with cirrhosis, with relatively high proportions of more severe grades II and III.This could be explained by the higher Vol:.(1234567890 www.nature.com/scientificreports/prevalence of organ failure in AP with CLD.A similar pattern could be observed in our data, where the pooled OR for single organ failure was 2.59 times higher and OR for multi-organ failure was 1.37 times higher in the CLD group.All these data suggest that the stage of CLD plays a crucial role in determining the prognosis of AP, despite the fact that the level of evidence is still very low.Increased odds of local complications, including ANC, APFC, and PC, were observed.The odds of WON could not be determined due to insufficient data.The most interesting finding from a prognostic perspective is the 2.53-fold increase in the odds of ANC, as the presence of which increases mortality by up to 15%.If ANC becomes infected (IPN), mortality increases to 29%.Moreover, Simons-Linares et al. 32 reported an OR of 2.45, p = 0.004 for infected pancreatic necrosis (IPN) in AP patients with cirrhosis 55 .The higher odds of local complications could contribute to worsening mortality in patients with CLD.
Furthermore, infections are also well-known common complications of CLD and could be another possible explanation for worse outcomes.Vogel et al. 35 reported sepsis-associated MODS as a leading cause of death in their cohort, whereas several other authors reported an increased prevalence of infections 39,56 , need for antibiotics 29 , interventions due to infection 35 , infected pancreatic necrosis 32 , and the prevalence of sepsis 30,33,34 in AP patients with CLD.The present meta-analysis also attempted to analyzed infectious complications, but due to large heterogeneity in definitions, overlapping populations, and unclear definitions, it was impossible to pool this data.Despite this, infections appear to play a significant role in AP patients with CLD, and the early use of antibiotics in these patients seems to be warranted.   .This theory is supported by our finding that the odds of SIRS are doubled in the CLD group.It remains uncertain if the effect of CLD is observed independently of the confounders.The analysis only with the adjusted models was attempted.However, due to the lack of these models in current literature, this became impossible.In the current literature, data on the adjusted models was found only for Mortality, Organ Failure, MODS, and SIRS.We used this data to perform a sensitivity analysis, where the adjusted model OR was pooled with the rest of the raw and not-adjusted OR values.For details, see the supplementary material (Supplementary Figs.S26-33).Overall, we found, that the effect sizes in the individual study level and the pooled effect sizes did not differ significantly between the adjusted and non-adjusted models.We did not detect any clinically meaningful difference between the adjusted and non-adjusted models.However, no definitive conclusion could be drawn due to the poor reporting of confounders in articles.
Throughout the results, relatively high level of clinical and statistical heterogeneity of the studies was observed.To address it, sensitivity analysis with a leave-one-out analysis was conducted.A few studies were found to be influential: affecting the pooled effect size, heterogeneity statistics, or other parameters in a relevant amount.Excluding these specific studies reduced heterogeneity in organ failure, SIRS, and APFC outcomes.For organ failure, the I 2 value decreased from 43 to 8% by excluding the study by Vogel et al. 35 , likely because it was the only study using the Sequential Organ Failure Assessment classification (SOFA).In other cases, the reason remains unclear (Supplementary Figs.S16-25).No influential publication was detected for in-hospital mortality.

Strengths and limitations
This meta-analysis has several strengths.Firstly, it employs large sample size and a diverse population from European, American, and Asian countries, making these data more applicable in practice.Furthermore, the study employs rigorous methodology with a pre-registered protocol and an assessment of the level of certainty by GRADEpro (Supplementary Table S3), which increases the reliability of the results.
However, several limitations must be noted.First, most of the data come from retrospective or cross-sectional studies, which limits the level of evidence.Second, the nature of the datasets reported in the current literature did not allow for more detailed subgrouping according to the specific etiology or stage of liver fibrosis.The additional limitation is the relatively high number of studies with moderate or high ROB.To address this, an analysis was conducted using only studies with a low risk of bias.This significantly changed heterogeneity only in the outcomes for systemic complications but did not affect other outcomes.The effect size remained the same (Supplementary Figs.S10-15).

Implications for practice
These results imply that CLD is a significant risk factor for worse outcomes in AP.Physicians should be aware of this, especially in the early phase of AP, for proper risk stratification of these patients.AP patients with concomitant AP and CLD require more attention and rigorous monitoring during hospitalization, as they are at higher risk of more severe forms of diseases and of both local and systemic complications.

Implications for research
The proclivity for simultaneous occurrence of AP and CLD and worse outcomes highlights the importance of further research into this relationship.Recent publications have shown that the rapid application of science to medical practice can dramatically improve healthcare, including reductions in duration and cost of hospitalizations and better patient outcomes 60 .Academia Europaea has suggested that the translational medicine cycle is one of the most effective strategies to achieve this goal 61 .Many unanswered questions about concomitant AP and CLD could benefit from this approach.One of the most pressing issues is the lack of prospective data, another is the exact role of infections and the possible role of prophylactic ATB and albumin substitutions.Inspiration could be drawn from well-established protocols for variceal bleeding and spontaneous bacterial peritonitis.Furthermore, CLD could be incorporated into future prognostic models of AP severity.

Conclusion
Chronic liver disease is an important risk factor for unfavorable outcomes in patients with AP, leading to higher mortality and increased odds of local and systemic complications.

Methods
The Cochrane Handbook was followed for standards and methods 62 , and PRISMA 63 for reporting (Supplementary Table S2).The protocol was registered in advance on Prospero with code IDCRD42022368905.

Eligibility criteria
Studies were included if they met the following criteria: the study reported on a population of adult patients diagnosed with AP, where patients exposed to CLD were compared to control patients without records or signs of CLD.The primary outcome was mortality; secondary outcomes were severity of AP, local or systemic complications, and the length of hospital stay.CLD was defined as liver disease lasting more than six months.Randomized control trials, retrospective and prospective cohorts were included, while case reports or series were excluded.

Figure 1 .
Figure 1.Prisma 2020 flow diagram of the screening and selection process.

Figure 4 .
Figure 4. Forest plot of the pooled odds ratio for organ failure.OR, odds ratio; CI, confidence interval; CLD, chronic liver diseases.

Figure 5 .Figure 6 .
Figure 5. Forest plot of the pooled odds ratio for organ failure by organ type.(A) OR for renal failure; (B) OR for respiratory failure; (C) OR for cardiac failure.OR, odds ratio; CI, confidence interval; CLD, chronic liver diseases.

Figure 7 .
Figure 7. Summary plot of the risk of bias by the Robvis tool.

Table 1 .
Main characteristics of the included studies in the systematic review and meta-analysis.AAP, alcohol-induced acute pancreatitis; AFC, acute peripancreatic fluid collections; AFLD, Alcoholic fatty liver disease; ANC, Acute necrotic collections; CLD, chronic liver disease; CRP, C-reactive protein; CT, computed tomography; CT Liver/spleen, ratio of density of liver to spleen; ICD, The International Classification of Diseases; IPN, Infectious pancreatic necrosis; LOS, Length of hospital stay; MAFLD, Metabolic associated fatty liver disease; MRI, Magnetic resonance imaging; NA, not available; NAFLD, Non-alcoholic fatty liver disease; ODS, Multiple Organ Dysfunction Syndrome; PC, Pancreatic pseudocysts; SD, standard deviation; SIRS, Systemic Inflammatory Response Syndrome; US, Ultrasonography; WON, Walled-off necrosis.a Parameters represented as mean with standard deviation, or median with range (minimum and maximum).b Study included only in systematic review.c Conference abstract.
Figure 2.Forest plot of the pooled odds ratio of severe acute pancreatitis.OR, odds ratio; CI, confidence interval; CIL, lower limit of confidence interval; CIU, upper limit of confidence interval; CLD, chronic liver diseases.LOWFigure 3.Forest plot of the pooled odds ratio of in-hospital mortality.OR, odds ratio; CI, confidence interval; CIL, lower limit of confidence interval; CIU, upper limit of confidence interval; CLD, chronic liver diseases.