Fatty Liver Disease and Non-Alcoholic Fatty Liver Disease Worsen the Outcome in Acute Pancreatitis: A Systematic Review and Meta-Analysis

The prevalence of fatty liver disease (FLD) and that of non-alcoholic fatty liver disease (NAFLD) share some risk factors known to exacerbate the course of acute pancreatitis (AP). This meta-analysis aimed to investigate whether FLD or NAFLD carry a higher risk of untoward outcomes in AP. In accordance with PRISMA guidelines, we performed a systematic search in seven medical databases for cohort studies that compared the outcomes of AP for the presence of FLD or NAFLD, and we calculated pooled odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval (CI). We included 13 articles in our meta-analysis. AP patients with FLD were more likely to die (5.09% vs 1.89%, OR = 3.56, CI = 1.75–7.22), develop severe AP (16.33% vs 7.87%, OR = 2.67, CI = 2.01–3.56), necrotizing pancreatitis (34.83% vs 15.75%, OR = 3.08, CI = 2.44–3.90) and had longer in-hospital stay (10.8 vs 9.2 days, WMD = 1.46, OR = 0.54–2.39). Patients with NAFLD were more likely to have severe AP and longer hospital stay. Both FLD and NAFLD proved to be independent risk factors of a more severe disease course (OR = 3.68, CI = 2.16–6.29 and OR = 3.39, CI = 1.52–7.56 for moderate/ severe vs. mild AP, respectively). FLD and NAFLD worsen the outcomes of AP, which suggests that incorporating FLD or NAFLD into prognostic scoring systems of AP outcomes might improve the prediction of severity and contribute to a more individualized patient care.


Rationale 3
Describe the rationale for the review in the context of what is already known. 1-2

Objectives 4
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 2

Protocol and
registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. 2 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 2 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

2-3
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 3

Data items 11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 3

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 3

Study characteristics 18
For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 4 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

9-10
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). 10 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). 11

Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for future research. 11-12

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. Exclusion: "(1) previous history of pancreatic disease, including acute pancreatitis, chronic pancreatitis, pancreatic cancer; (2) those with chronic heart disease; (3) those with chronic renal failure; (4) with chronic liver Those with dysfunction; (5) those with a history of malignancy; (6) those with a history of diabetes; (7) those with missing or incomplete data." Exclusion: "relapse of acute pancreatitis or with an exacerbation of chronic pancreatitis, patients with incomplete medical data, patients with active malignancy, those who were younger than 18 years and those who were receiving medications that can cause liver steatosis (corticosteroids, amiodarone, etc.) unknown etiology" Exclusion: "other causes of chronic steatosis; consummation of more than 14 alcohol drinks/week in women and more than 21 alcohol drinks/week in men was considered as excessive alcohol consumption; laboratory results indicating on possible alcohol consumption" Inclusion: "patients that were treated at University Medicine Greifswald with the main diagnosis acute pancreatitis (ICD-10-GM: K85.xx) or chronic pancreatitis ICD-10-GM: K86.0 (alcoholic chronic pancreatitis) or K.86.1 (chronic pancreatitis by other origin) between 2006 and 2011." Exclusion: "Patients with incomplete or inconsistent information from the HIS were excluded. When data from the questionnaire were incomplete, the existing information was still analyzed in bivariate analyses but could not include in multivariate analyses because of the test design."     Figure S1.

Results
On full-text assessment, we excluded six studies due to inappropriate study design or inappropriate inclusion criteria. Exclusion criteria from the qualitative synthesis included: one previous meta-analysis, one review that assessed the rate of FLD in AP patients, two studies reported only on severe FLD (defined by hepatic attenuation index -HAI<0.5) cases and one case-report. A study that utilized the Nationwide Inpatient Sample database of the United States of America to assess the association between NAFLD and AP severity was also excluded because the un-proportionally low rate of NAFLD cases.
We could not include two articles in quantitative synthesis because of a lack of data. Only one study reported on long-term outcomes and one on hospital readmission.
Details of the parameters included in multivariate analysis in the included articles are summarized in Table S3.

Risk of bias assessment between studies
Based on our analysis Hao YM [3], Wang S. et al. [11] and Satapathy S. et al. [9] showed the worse results with having multiple moderate and high-risk domains. The domain of "study participation" was the best-rated, as only one study carried a high and two studies carried moderate risk of bias. In contrast, the domain of 'study confounding' was the worst rated, since multiple studies did not report how the important confounders were accounted for and whether an appropriate method was used for handling missing data.